LIMK1/cofilin信号通路调控BDNF诱导的轴突生长和厌恶性记忆消退的机制研究
|
摘要
背景：
肌动蛋白(Actin)是一种细胞骨架蛋白,它在细胞生理功能方面发挥了重要的作用,包括胞浆分裂、内吞、神经生长等。肌动蛋白发挥它的生物学功能主要是通过肌动蛋白重组(Actin remodeling),即单体肌动蛋白(G-actin)和丝状肌动蛋白(F-actin)之间的动态变化。肌动蛋白重组受多种蛋白的调控,例如ADF/cofilin、Arp2/3、 Eps8、Profilin、myosin Ⅱ、myosin Ⅴ。由于ADF/cofilin广泛分布于所有的真核细胞,并且对肌动蛋白重组具有最直接的调控功能,且对发育具有重要的作用,逐渐成为研究肿瘤转移、生殖系统疾病、循环系统疾病、神经系统疾病等的研究热点。
神经细胞发挥正常的生理功能依赖于神经细胞正常的生长发育及分化。在神经元极性分化的过程中,轴突的生长早于树突,轴突末端的膨大称为生长锥(Growth cone),由丝状伪足(Filopodia)和板状伪足(Lamellipodia)构成,它们的动态变化指引了轴突生长的方向。在轴突生长锥的胞膜附近富含肌动蛋白网状结构,肌动蛋白动态变化是轴突生长的基础。神经营养因子尤其是目前研究最多的BDNF对神经元的生长、分化、存活及突触可塑性方面具有非常重要的作用。尽管如此,BDNF如何调控肌动蛋白重组促进神经元生长发育的具体机制有待进一步研究。
在成年哺乳动物神经系统中,神经元绝大多数以化学性突触的形式互联,形成神经元网络。化学性突触大多是由突触前神经元的轴突末梢和突触后神经元的树突棘及两者之间的突触间隙组成。这种突触具有可塑性,表现为突触前膜释放神经递质具有可调控性,突触后膜的形态及受体数目具有可变性。肌动蛋白网络作为细胞骨架成分之一是维持突触形态结构基础,肌动蛋白细胞骨架的解聚和聚合与突触后膜AMPA受体内吞和上膜也有密切的联系。肌动蛋白的重组具有直接调节突触传递效率的作用,包括长时程增强(LTP)与长时程减弱(LTD),因此肌动蛋白的动态变化是突触可塑性及学习记忆的基础。虽然cofilin是调节肌动蛋白重组的关键分子,但是cofilin调控学习记忆的具体机制仍然不清楚
目的：
1.分析LIMK1/cofilin信号通路与BDNF及其受体TrkB的关系,并深入探讨LIMK1/cofilin信号通路参与调控BDNF诱导的轴突生长的分子机制,为进一步研究BDNF基因突变导致神经细胞生长发育异常疾病的干预措施提供理论依据。
2.分析LIMK1/cofilin信号通路在学习记忆方面的作用,并深入研究条件性厌恶记忆消退过程IrL脑区中LIMK1/cofilin信号通路的作用及其机制,为今后研究以LIMK1/cofilin为靶点的临床相关疾病的治疗措施提供新思路。
方法
1. LIMK1/cofilin信号通路调控BDNF诱导的轴突生长的机制研究
1.1LIMK1与TrkB之间相互作用的检测
通过免疫共沉淀的方法分别检测外源性过表达LIMK1与TrkB的HEK293细胞裂解液和正常大鼠脑组织或神经元裂解液中LIMK1与TrkB能否相互结合。为了排除细胞裂解后使不同亚细胞器中的蛋白释放入裂解液中出现人为的结合,我们采用免疫荧光共定位的方法检测两种蛋白是否存在空间上的重叠性。从而证明TrkB与LIMK1在胞内发生相互作用的可能。
1.2分析BDNF短时间刺激海马神经元对LIMK1蛋白的影响
体外培养的海马神经元用BDNF刺激30分钟,通过蛋白免疫印迹的方法检测裂解液中LIMK1的磷酸化及二聚化情况,来反映LIMK1的活性变化。另外分离海马神经元的胞浆和胞膜成分,分别检测两种成分中LIMK1含量的变化,来反映LIMK1在胞内的分布情况。
1.3TrkB与LIMK1发生相互作用的序列分析
采用逐步缺失的方法,设计TrkB不同氨基酸序列突变体,分别和LIMK1进行外源性的免疫共沉淀实验,筛选出TrkB上与LIMK1相互结合的氨基酸序列,并将该序列嫁接到不能与LIMK1结合的T1蛋白上,再次进行外源性的免疫共沉淀实验,从而证明该氨基酸序列与LIMK1结合的必要性和充分性。
1.4设计特异性抑制剂干扰TrkB与LIMK1的结合
将筛选出来的TrkB中与LIMK1结合的氨基酸序列与具有穿膜作用短肽Tat进行融合,并对其进行生物素标记,以便于检测。用免疫荧光染色的方法检测该人工合成的融合肽是否能够进入胞内,用外源性和内源性免疫共沉淀的方法检测该抑制剂的干扰效率。并应用该抑制剂后再次检测BDNF刺激对LIMK1的生化特点的影响,来反映BDNF引起的LIMK1的各种变化是否依赖于TrkB与LIMK1的相互作用。
1.5分析BDNF长时间刺激海马神经元对LIMK1蛋白的影响
体外培养的海马神经元给予蛋白合成抑制剂后,再用BDNF刺激不同时间,最长达20h,检测LIMK1含量的变化,来反映BDNF刺激对LIMK1降解的影响。
1.6分析药物干预TrkB与LIMK1相互作用对BDNF诱导的轴突生长的影响
在神经元中过表达LIMK1或用小干扰RNA(siRNA)抑制LIMK1的表达,然后用免疫荧光染色的方法检测BDNF刺激对轴突生长的作用,来反映BDNF促进轴突生长的作用是否依赖于LIMK1。然后用人工合成的Tat融合肽干扰内源性TrkB与LIMK1的相互作用,检测BDNF对轴突生长的促进作用。此外,通过免疫荧光染色方法检测轴突生长锥(Growth cone)中LIMK1、cofilin的磷酸化及肌动蛋白actin的聚合情况,来反映LIMK1/cofilin信号通路调控轴突生长的下游机制。
2. LIMK1/cofilin信号通路调控条件性厌恶记忆消退的机制研究
2.1条件性味觉厌恶记忆模型的建立及各脑区中cofilin活性检测
建立条件性味觉厌恶(CTA)行为学模型,分别在CTA记忆获得和消退过程的不同时间点取不同区域脑组织,采用蛋白免疫印迹的方法检测cofilin的磷酸化水平变化及cofilin的上游激酶LIMK1和磷酸酶SSH1的磷酸化变化情况,来反映cofilin活性变化的分子机制。
2.2测试药物干预对行为学的影响
在大鼠IrL脑区内埋管进行微量注射Tat融合肽抑制或增强cofilin活性及抑制GluA2上膜,观察对条件性味觉厌恶记忆及恐惧记忆消退的影响,来进一步证实cofilin活性对记忆消退的重要性及其机制。
2.3检测突触体及其膜表面中谷氨酸受体的变化
从脑组织中抽提突触体进行裂解检测各亚型AMPA受体及NMDA受体的含量变化,或将提取的突触体进行膜表面蛋白的生物素标记,用含有亲和素的琼脂糖珠子进行沉淀,获得膜表面蛋白的混合溶液,然后用蛋白免疫印迹的方法检测突触体膜表面各谷氨酸受体亚型的含量变化。
2.4观察突触体形态结构的变化
采用高尔基染色的方法观察CTA记忆消退过程中及药物干预cofilin活性后树突棘形态和密度的变化,来判断CTA记忆消退过程中突触形态结构的变化是否和突触传递效率的变化相同步。
结果
1. LIMK1/cofilin信号通路调控BDNF诱导的轴突生长的机制研究
1.1LIMK1与TrkB之间存在相互作用
在体外培养的HEK293细胞中过表达HA标记的LIMK1(HA-LIMK1)和Flag标记的TrkB (Flag-TrkB),进行免疫共沉淀实验。HA-LIMK1可以将Flag-TrkB沉淀下来,反之用Flag-TrkB也可以将HA-LIMK1免疫沉淀下来。此外,在体外培养的海马神经元中,用免疫荧光染色的方法发现红色荧光标记的LIMK1与绿色荧光标记的TrkB存在部分重叠。
1.2BDNF短时间刺激体外培养的海马神经元可以引起LIMK1磷酸化、二聚化及胞内分布情况的变化
在体外培养的海马神经元的培养液中加入BDNF刺激30分钟,收集细胞裂解液,通过蛋白免疫印迹的方法检测到p-LIMK1(?)曾加。在收集的蛋白裂解液中用不含p巯基乙醇和二巯基苏糖醇的上样缓冲液98℃加热,防止破坏二硫键,BDNF刺激后可以出现LIMK1的二聚化。此外,分别抽提胞浆成分和胞膜成分,BDNF刺激30分钟引起胞浆中的LIMK1降低,胞膜中LIMK1水平升高。
1.3TrkB蛋白JM区域中的9个氨基酸介导与LIMK1蛋白的结合
将TrkB蛋白的胞内域进行逐步缺失突变,发现缺失C末端(ACT)、缺失激酶区(ATK)后,TrkB仍能与LIMK1结合,但是进一步缺失近膜区即胞内域全部缺失(JM0)后,则不能与LIMK1结合。然后将JM区域细分成5个小片段,仍然采用逐步缺失突变的方法,发现JM5、JM4能和LIMK1结合,而JM3、JM2、JM1及JM0不能与LIMK1结合,因此JM4与JM3之间的差别序列(VIENPQYFG)为介导TrkB与LIMK1结合的关键序列。此外,我们将这9个氨基酸嫁接到T1蛋白上,发现原本不能与LIMK1结合的T1也可以与LIMK1结合。
1.4干扰TrkB与LIMK1的结合抑制BDNF引起的LIMK1的磷酸化、二聚化及胞内分布的变化
将筛选出的介导TrkB与LIMK1结合的氨基酸序列嫁接到穿膜肽Tat上(Tat-JMBox4),发现该融合肽能成功的进入神经细胞内,并能有效抑制TrkB与LIMK1的相互结合。用该人工合成的短肽封闭TrkB与LIMK1的相互作用后,发现BDNF引起的LIMK1的磷酸化、二聚化及胞内分布变化的现象被抑制。
1.5BDNF长时间刺激可以延缓LIMK1的降解
在体外培养的海马神经元的培养液中,加入BDNF分别刺激1、5、15、20h后收集裂解液,发现LIMK1的蛋白水平升高。如果在加入BDNF之前,提前加入蛋白合成抑制剂放线菌酮(cycloheximide),发现加入BDNF组比不加BDNF组,LIMK1的半衰期延长,而用Tat-JMBox4干扰TrkB与LIMK1的相互作用后,BDNF对LIMK1的稳定作用被抑制。
1.6BDNF诱导轴突生长依赖于TrkB与LIMK1的相互作用
在体外培养的海马神经元中过表达LIMK1或者用小干扰RNA (siRNA)干扰LIMK1的表达,然后再用BDNF刺激,发现过表达LIMK1组神经元轴突快速生长,而干扰LIMK1表达后,BDNF促进轴突生长的作用被抑制。而且,用Tat-JMBox4抑制TrkB与LIMK1相互作用后,BDNF诱导轴突生长的功能被抑制。
2. LIMK1/cofilin信号通路调控条件性厌恶记忆消退的机制研究
2.1CTA记忆消退过程IrL脑区中cofilin活性增高
消退测试第一天(E1-)不同时间点取脑组织进行检测,发现p-cofilin在测试后0.5h和2h明显升高。第三天消退测试(E3)后0.5h与第一天进行对比,发现p-cofilin明显降低,即cofilin活性增高。
2.2CTA记忆消退过程中p-LIMK1和p-SSH1水平均降低
消退第三天(E3)p-LIMK1和p-SSH1水平比消退第一天(E1)明显降低,即在CTA记忆消退过程中LIMK1活性降低而SSH1活性升高。
2.3药物千预cofilin活性影响CTA记忆的消退进程
在前三次记忆消退测试后,在IrL脑区立即注射Tat-Ser3增加cofilin活性可以加速CTA记忆消退,而注射Tat-pSer3降低cofilin活性则阻碍CTA记忆消退。然而,在前三次记忆消退后4h,在IrL脑区中给予这两种药物均对CTA记忆消退没有影响。
2.4CTA记忆消退过程中突触体及其膜表面AMPA受体含量增加
在CTA记忆消退过程中,IrL脑区的突触体及其膜表面GluA1和GluA2的含量显著升高,而GluA3、GluA4及NR-1则没有明显变化。但是,CTA记忆消退过程中,IrL脑区总的脑组织裂解液中GluAl和GluA2的含量没有变化。
2.5药物干预cofilin活性影响突触后AMPA受体水平
在CTA记忆消退的前三天,用Tat-Ser3增加cofilin活性,可以引起GluA1和GluA2在突触体膜表面的含量,而用Tat-pSer3抑制cofilin活性则显著降低了GluA1和GluA2在突触体膜表面的含量。
2.6CTA记忆消退过程中突触形态结构没有明显变化
在CTA记忆消退过程中,树突棘头颈比(head/neck ratio)及树突棘的密度均未发生明显的变化,即使用Tat短肽干扰cofilin的活性也对树突棘的形态及密度没有影响。
2.7GluA2上膜抑制剂阻碍CTA记忆的消退
在CTA记忆消退前三天给予GluA2上膜的抑制剂(Tat-pepR845A),或者在给予Tat-Ser3增加cofilin活性的同时给予GluA2上膜的抑制剂,发现CTA记忆消退进程减慢。
结论
1. BDNF引起LIMK1蛋白发生磷酸化、二聚化及胞内重新分布的现象依赖于TrkB与LIMK1的相互作用,LIMK1蛋白的二聚化使LIMK1蛋白稳定性增加,活性增强,通过磷酸化cofilin蛋白促进肌动蛋白的聚合,从而促进轴突的生长。
2.记忆消退过程中激酶LIMK1蛋白和磷酸酶SSH1蛋白的协同作用,使得cofilin蛋白活性增强,虽然cofilin蛋白活性的增加没有引起树突棘的大小和密度发生变化,但是cofilin蛋白活性的增高促进了AMPA受体向突触体及膜表面转运,引起突触后传递效率增加,从而加速了记忆消退进程。
创新点
1. LIMK1/cofilin信号通路调控BDNF诱导的轴突生长的机制研究
1.1研究发现了一种能与TrkB蛋白相互作用的新分子即LIMK1蛋白,并且找出了TrkB分子中与LIMK1相结合的具体的氨基酸序列。
1.2发现BDNF刺激海马神经元对LIMK1存在两种不同的影响,即短时间作用可促进LIMK1活性增加并引起LIMK1在胞内重新分布,长时间刺激可稳定LIMK1蛋白延缓其降解。
1.3研究发现BDNF诱导的轴突的生长依赖于TrkB蛋白与LIMK1蛋白的相互作用。
2LIMK1/cofilin信号通路调控条件性厌恶记忆消退的机制研究
2.1发现了cofilin调控记忆消退的具体分子机制。
2.2研究发现突触传递效率的可塑性与突触形态结构的可塑性两者没有直接的相关性。
Background
Actin is a cytoskeletal protein, which plays important roles in cell physiological functions such as cytokinesis, endocytosis, neurite extension and synaptic plasticity. Actin exerting its physiological function depends on actin remodeling, that is dynamic changes of globular actin (G-actin) and filamentous actin (F-actin). Actin remodeling is regulated by many proteins including ADF/cofilin, Arp2/3, Eps8, Profilin, myosin Ⅱ and myosin Ⅴ. Since ADF/cofilin is ubiquitously expressed in eukaryote, directly regulating actin remodeling and is essential for growth and development, it is gradually becoming research focus in the fields of tumor metastasis, diseases of reproductive system, diseases of circulatory system and disorder of nervous system.
Neurons play physiological functions requiring properly growth and differentiation. The outgrowth of axons is earlier than dendrites. The terminal enlargement of axon is growth cone, composing filopodia and lamellipodia. Growth cone is rich of actin network especially beneath the membrane. Actin dynamic is the basis of neurite extension. Neurotrophins especially the most studied BDNF are important for neuronal growth, differentiation, survival and synaptic plasticity. However, the exact mechanism for BDNF promoting neurite outgrowth is pending further study.
In the central nervous system (CNS) in adults, the vast majority of neurons form a complex network in the form of chemical synapse interconnection. Chemical synapses, which are specialized junctions between axonal terminals and dendritic spines, have synaptic plasticity. Synaptic plasticity is the ability of synapse to change in strength responding to either use or disuse of transmission over synaptic pathways. Synaptic plasticity results from the alteration of neurotransmitter release, the number of receptors located on synapse and the morphology of dendritic spines. Actin dynamics is not only the basis of synaptic morphology but also closely linked to postsynaptic AMPA receptor endocytosis and insertion. Actin dynamics, which directly modulates synaptic transmission efficiency including LTP and LID, is the foundation of learning and memory. Although cofilin is the key molecule in regulating actin reorganization, the specific mechanism for cofilin regulating learning and memory remains unclear.
Objective
1. To explore the relationship between LIMK1/cofilin signaling pathway and BDNF/TrkB signaling pathway, and identify the molecular mechanism for BDNF induced axonal elongation. So that it provides the theory basis for deeply researching the therapy of BDNF mutant induced abnormalities in the nervous system.
2. To study the effect of LIMK1/cofilin signaling pathway on aversive memory extinction, and provide the theory basis for searching a potential treatment strategy for memory disorders.
Methods
1. The mechanism for LIMK1/cofilin signaling pathway regulating BDNF induced axonal elongation
1.1Detection of interaction between LIMK1and TrkB
48h after electroporation with HA-LIMK1and Flag-TrkB, HEK293cells were lysed and collected for co-immunoprecipitation and immunoblotting. We performed immunostaining experiments to compare the subcellular distribution of LIMK1and TrkB.
1.2The short term effect of BDNF on LIMK1
After serum starvation, cultured neurons were stimulated with BDNF for30min. cell lysates were collected for SDS-PAGE to detect phosphorylation of LIMK1. Cell extracts were subjected to SDS-PAGE in the absence or presence of dithiothreitol, and then immunoblotted with anti-LIMK1to test homo-dimerization level of LIMK1. Additionally, neuron lysates were separated into membrane and cytosol fraction to examine the distribution of LIMK1before and after BDNF treatment.
1.3Sequence analysis of TrkB/LIMK1interaction
Various sequences were gradually deleted from the full-length of TrkB (TrkB-FL), and co-immunoprecipitation was carried out between TrkB mutants and LIMK1. The responsible sequence for TrkB/LIMK1interaction was linked to T1protein which could not associate with LIMK1. Then we detected the interaction between chimeric receptor and LIMK1.
1.4Design the specific inhibitor for TrkB/LIMK1interaction
Based on our previous TrkB/LIMK1interaction domain mapping study, we used a synthesized peptide consisting of the9-amino acid sequence of JMBox4in TrkB fused to the membrane permeability peptide-Tat. We examined the membrane permeability by immunostaining and tested the interfering efficiency by co-immunoprecipitation endogenously and exogenously.
1.5The long term effect of BDNF on LIMK1
We detected the LIMK1level after5-20h BDNF treatment. To determine whether BDNF has an influence on LIMK1stability, we analyzed the degradation rate of the LIMK1protein in primary cultured hippocampal neurons pretreated with cycloheximide (CHX).
1.6Effect of Tat-JMBox4on BDNF induced axonal elongation
To identify the importance of LIMK1in BDNF induced axonal elongation, we tested the effect of BDNF on axonal length of the cultured neurons that were transfected with HA-LIMK1or LIMK1siRNA, respectively. Then we examined the effect of BDNF on axonal length of neurons when TrkB/LIMK1interplay was blocked by Tat-JMBox4. In addition, we detected the level of p-LIMK1, p-cofilin and F-actin in growth cone before and after BDNF treatment.
2. The mechanism for LIMK1/cofilin signaling pathway regulating aversive memory extinction
2.1Establish the experimental model and test cofilin activity
We established the CTA model and recorded the aversive index (AI). We collected different brain regions at vary times, and detected cofilin activity by Western Blot analysis. We tested phosphorylation of LIMK1and SSH1as well.
2.2The behavior change after Tat-peptide treatment
We used synthetic peptides to alter cofilin activity or inhibit GluA2synaptic insertion. Specifically Tat-Ser3can enhance cofilin activity, Tat-pSer3can weaken cofilin activity and Tat-pepR845A can block GluA2synaptic insertion. We examined the behavior change after microinjection of drugs.
2.3Expression level of AMPARs in synapse and postsynaptic membrane
We isolated crude particulate fraction of synapse termed synaptoneurosome (SNS) from the IrL, part of SNS was surface biotinylated and subsequently precipitated with neutravidin-agarose conjugate. All subunits of AMPA receptors (AMPARs) and NR1subunit of NMDA receptor were detected by immunoblotting.
2.4Morphological changes of synapse
We carried out Golgi staining to observe the structure changes including ratios of spine's head to neck and spine density.
Results
1. The mechanism for LIMK1/cofilin signaling pathway regulating BDNF induced axonal elongation
1.1LIMK1interacts with TrkB receptor
LIMK1associates with TrkB receptor endogenously and exogenously. In addition, LIMK1co-localizes with the TrkB receptor in cultured hippocampal neurons.
1.2Short term treatment of BDNF induces LIMK1phosphorylation, homo-dimerization and redistribution
30min after BDNF treatment, phosphorylation (Thr-508) of LIMK1was increased in a TrkB tyrosine kinase activity-dependent manner. BDNF induced LIMK1homo-dimerization independent of TrkB receptor tyrosine kinase activity. Additionally, BDNF stimuli increased membrane-associated LIMK1and decreased cytosolic LIMK1.
1.3JMBox4region in TrkB is responsible for TrkB/LIMK1interaction
We found that JMBox4region which is the9-amino acid sequence between JM3and JM4is necessary and sufficient for TrkB/LIMK1interaction.
1.4The short term effect of BDNF on LIMK1is dependent on TrkB/LIMK1interaction
The synthesized peptide (Tat-JMBox4) which could efficiently block TrkB/LIMK1interaction disrupted BDNF induced LIMK1phosphorylation, homo-dimerization and redistribution.
1.5Long term treatment of BDNF stabilizes LIMK1protein
We found that endogenous LIMK1was gradually degraded with a half-life of～20h when CHX was present. However, when treated with BDNF, the half-life of LIMK1protein was prolonged to>20h. The effect of BDNF on LIMK1degradation was also blocked by Tat-JMBox4.
1.7TrkB/LIMK1interaction is required for BDNF induced axonal growth
We found that up-regulation of LIMK1levels increase axonal length whereas siRNA knocking down LIMK1levels decreased axonal length. Neurons over-expressing LIMK1displayed significantly longer axon in the presence of BDNF, whereas neurons transfected with LIMK1siRNA lost their responsiveness to BDNF. Moreover, we found that the BDNF induced axonal extension was blocked by Tat-JMBox4treatment.
2. The mechanism for LIMK1/cofilin signaling pathway regulating aversive memory extinction
2.1CTA consecutive extinction training enhances cofilin activity in the IrL
We observe that the rats exhibited a transient increase in cofilin phosphorylation at30min and120min after E1, peaking at30min and returning to baseline at240min. Hence, we selected the time point30min after extinction training for measuring the p-cofilin during CTA extinction. Immunoblotting analysis showed that the p-cofilin levels were markedly reduced after E3when compared with E1.
2.2LIMK1and SSH1coordinate to regulate cofilin activity during extinction
Since LIMK1is activated by its Thr508phosphorylation and SSH1is inactivated by its Ser978phosphorylation, we used specific antibodies to determine the activity changes of LIMK1and SSH1. We observed that extinction training decreased LIMK1activity whereas increased SSH1activity.
2.3Cofilin activity is required for CTA extinction
Compared with Tat control, Tat-S3microinfusion immediately after extinction training significantly facilitated memory extinction, while Tat-pS3had the opposite effect. However, we observed that administration of Tat-Ser3or Tat-pSer3peptide into the IrL4h after E1-E3had no effect on memory extinction.
2.4Memory extinction facilitates GluAl and GluA2synaptic trafficking in the IrL
The levels of GluAl and GluA2in the SNS fraction were notably increased, whereas the level of GluA3, GluA4and NR1were not significantly changed during memory extinction. In a crude homogenized IrL fraction, the expression levels of GluAl and GluA2were unchanged. We also observed an increase in the surface levels of GluA1and GluA2subunits but no other subunits extinction.2.5cofilin activity regulates GluAl and GluA2synaptic trafficking during memory extinction We found that Tat-Ser3infusion immediately after exposure to E1-E3significantly increased the surface levels of GluA1and GluA2. On the contrary, Tat-pSer3injection decreased not only synaptic but also postsynaptic surface levels of GluAl and GluA2during memory extinction.
2.6Morphology of synapse is unchanged during memory extinction
Neither the three consecutive extinction training nor the additional regulation of cofilin activity by Tat-Ser3or Tat-pSer3could change the ratios of spine's head to neck and spine density during memory extinction.
2.7Inhibition of GluA2membrane insertion leads to memory extinction impairment
We observed that microinjection of Tat-pepR845A which could inhibit GluA2-containing AMPA receptors synaptic membrane recruitment impaired memory extinction, even when we combined the microinfusion of Tat-pepR845A and Tat-Ser3.
Conclusion
1. Our study revealed that TrkB interacted with LIMK1via its JMBox4region. BDNF induced LIMK1dimerization and phosphorylation depended on TrkB/LIMKl interaction but not TrkB tyrosine kinase activity. Furthermore, we found that BDNF induced LIMK1dimerization and transactivation played an essential role in BDNF enhanced actin polymerization and axonal elongation. These findings provide insights into the mechanistic link between LIMK1regulated actin dynamic and BDNF induced axonal elongation.
2. In this study, we found memory extinction induced a temporal activation of cofilin, which stimulated GluA1and GluA2translocation to synapse and recruitment to postsynaptic membrane. Manipulating cofilin activity could alter extinction process, which was mediated by AMPARs synaptic trafficking. Finally we showed extinction triggered modifications of synaptic physiology and spine morphology are independent processes. Understanding the actin dynamics regulated relationship between synaptic physiological function (number of synaptic receptors) and spine structure (spine size and density) is crucial to our comprehension of mechanism of memory process.
Innovation
1. The mechanism for LIMK1/cofilin signaling pathway regulating BDNF induced axonal elongation
1.1We found LIMK1could associate with TrkB receptor for the first time.
1.2Our research showed that BDNF has short term effect and long term effect on LIMK1differently.
1.3This study revealed new mechanism for BDNF induced axonal elongation.
2. The mechanism for LIMK1/cofilin signaling pathway regulating aversive memory extinction
2.1Deeply explore the molecular mechanism for LIMK1/cofilin signaling pathway regulating memory extinction.
2.2We found that synaptic physiology and spine morphology are independent processes.
肌动蛋白(Actin)是一种细胞骨架蛋白,它在细胞生理功能方面发挥了重要的作用,包括胞浆分裂、内吞、神经生长等。肌动蛋白发挥它的生物学功能主要是通过肌动蛋白重组(Actin remodeling),即单体肌动蛋白(G-actin)和丝状肌动蛋白(F-actin)之间的动态变化。肌动蛋白重组受多种蛋白的调控,例如ADF/cofilin、Arp2/3、 Eps8、Profilin、myosin Ⅱ、myosin Ⅴ。由于ADF/cofilin广泛分布于所有的真核细胞,并且对肌动蛋白重组具有最直接的调控功能,且对发育具有重要的作用,逐渐成为研究肿瘤转移、生殖系统疾病、循环系统疾病、神经系统疾病等的研究热点。
神经细胞发挥正常的生理功能依赖于神经细胞正常的生长发育及分化。在神经元极性分化的过程中,轴突的生长早于树突,轴突末端的膨大称为生长锥(Growth cone),由丝状伪足(Filopodia)和板状伪足(Lamellipodia)构成,它们的动态变化指引了轴突生长的方向。在轴突生长锥的胞膜附近富含肌动蛋白网状结构,肌动蛋白动态变化是轴突生长的基础。神经营养因子尤其是目前研究最多的BDNF对神经元的生长、分化、存活及突触可塑性方面具有非常重要的作用。尽管如此,BDNF如何调控肌动蛋白重组促进神经元生长发育的具体机制有待进一步研究。
在成年哺乳动物神经系统中,神经元绝大多数以化学性突触的形式互联,形成神经元网络。化学性突触大多是由突触前神经元的轴突末梢和突触后神经元的树突棘及两者之间的突触间隙组成。这种突触具有可塑性,表现为突触前膜释放神经递质具有可调控性,突触后膜的形态及受体数目具有可变性。肌动蛋白网络作为细胞骨架成分之一是维持突触形态结构基础,肌动蛋白细胞骨架的解聚和聚合与突触后膜AMPA受体内吞和上膜也有密切的联系。肌动蛋白的重组具有直接调节突触传递效率的作用,包括长时程增强(LTP)与长时程减弱(LTD),因此肌动蛋白的动态变化是突触可塑性及学习记忆的基础。虽然cofilin是调节肌动蛋白重组的关键分子,但是cofilin调控学习记忆的具体机制仍然不清楚
目的：
1.分析LIMK1/cofilin信号通路与BDNF及其受体TrkB的关系,并深入探讨LIMK1/cofilin信号通路参与调控BDNF诱导的轴突生长的分子机制,为进一步研究BDNF基因突变导致神经细胞生长发育异常疾病的干预措施提供理论依据。
2.分析LIMK1/cofilin信号通路在学习记忆方面的作用,并深入研究条件性厌恶记忆消退过程IrL脑区中LIMK1/cofilin信号通路的作用及其机制,为今后研究以LIMK1/cofilin为靶点的临床相关疾病的治疗措施提供新思路。
方法
1. LIMK1/cofilin信号通路调控BDNF诱导的轴突生长的机制研究
1.1LIMK1与TrkB之间相互作用的检测
通过免疫共沉淀的方法分别检测外源性过表达LIMK1与TrkB的HEK293细胞裂解液和正常大鼠脑组织或神经元裂解液中LIMK1与TrkB能否相互结合。为了排除细胞裂解后使不同亚细胞器中的蛋白释放入裂解液中出现人为的结合,我们采用免疫荧光共定位的方法检测两种蛋白是否存在空间上的重叠性。从而证明TrkB与LIMK1在胞内发生相互作用的可能。
1.2分析BDNF短时间刺激海马神经元对LIMK1蛋白的影响
体外培养的海马神经元用BDNF刺激30分钟,通过蛋白免疫印迹的方法检测裂解液中LIMK1的磷酸化及二聚化情况,来反映LIMK1的活性变化。另外分离海马神经元的胞浆和胞膜成分,分别检测两种成分中LIMK1含量的变化,来反映LIMK1在胞内的分布情况。
1.3TrkB与LIMK1发生相互作用的序列分析
采用逐步缺失的方法,设计TrkB不同氨基酸序列突变体,分别和LIMK1进行外源性的免疫共沉淀实验,筛选出TrkB上与LIMK1相互结合的氨基酸序列,并将该序列嫁接到不能与LIMK1结合的T1蛋白上,再次进行外源性的免疫共沉淀实验,从而证明该氨基酸序列与LIMK1结合的必要性和充分性。
1.4设计特异性抑制剂干扰TrkB与LIMK1的结合
将筛选出来的TrkB中与LIMK1结合的氨基酸序列与具有穿膜作用短肽Tat进行融合,并对其进行生物素标记,以便于检测。用免疫荧光染色的方法检测该人工合成的融合肽是否能够进入胞内,用外源性和内源性免疫共沉淀的方法检测该抑制剂的干扰效率。并应用该抑制剂后再次检测BDNF刺激对LIMK1的生化特点的影响,来反映BDNF引起的LIMK1的各种变化是否依赖于TrkB与LIMK1的相互作用。
1.5分析BDNF长时间刺激海马神经元对LIMK1蛋白的影响
体外培养的海马神经元给予蛋白合成抑制剂后,再用BDNF刺激不同时间,最长达20h,检测LIMK1含量的变化,来反映BDNF刺激对LIMK1降解的影响。
1.6分析药物干预TrkB与LIMK1相互作用对BDNF诱导的轴突生长的影响
在神经元中过表达LIMK1或用小干扰RNA(siRNA)抑制LIMK1的表达,然后用免疫荧光染色的方法检测BDNF刺激对轴突生长的作用,来反映BDNF促进轴突生长的作用是否依赖于LIMK1。然后用人工合成的Tat融合肽干扰内源性TrkB与LIMK1的相互作用,检测BDNF对轴突生长的促进作用。此外,通过免疫荧光染色方法检测轴突生长锥(Growth cone)中LIMK1、cofilin的磷酸化及肌动蛋白actin的聚合情况,来反映LIMK1/cofilin信号通路调控轴突生长的下游机制。
2. LIMK1/cofilin信号通路调控条件性厌恶记忆消退的机制研究
2.1条件性味觉厌恶记忆模型的建立及各脑区中cofilin活性检测
建立条件性味觉厌恶(CTA)行为学模型,分别在CTA记忆获得和消退过程的不同时间点取不同区域脑组织,采用蛋白免疫印迹的方法检测cofilin的磷酸化水平变化及cofilin的上游激酶LIMK1和磷酸酶SSH1的磷酸化变化情况,来反映cofilin活性变化的分子机制。
2.2测试药物干预对行为学的影响
在大鼠IrL脑区内埋管进行微量注射Tat融合肽抑制或增强cofilin活性及抑制GluA2上膜,观察对条件性味觉厌恶记忆及恐惧记忆消退的影响,来进一步证实cofilin活性对记忆消退的重要性及其机制。
2.3检测突触体及其膜表面中谷氨酸受体的变化
从脑组织中抽提突触体进行裂解检测各亚型AMPA受体及NMDA受体的含量变化,或将提取的突触体进行膜表面蛋白的生物素标记,用含有亲和素的琼脂糖珠子进行沉淀,获得膜表面蛋白的混合溶液,然后用蛋白免疫印迹的方法检测突触体膜表面各谷氨酸受体亚型的含量变化。
2.4观察突触体形态结构的变化
采用高尔基染色的方法观察CTA记忆消退过程中及药物干预cofilin活性后树突棘形态和密度的变化,来判断CTA记忆消退过程中突触形态结构的变化是否和突触传递效率的变化相同步。
结果
1. LIMK1/cofilin信号通路调控BDNF诱导的轴突生长的机制研究
1.1LIMK1与TrkB之间存在相互作用
在体外培养的HEK293细胞中过表达HA标记的LIMK1(HA-LIMK1)和Flag标记的TrkB (Flag-TrkB),进行免疫共沉淀实验。HA-LIMK1可以将Flag-TrkB沉淀下来,反之用Flag-TrkB也可以将HA-LIMK1免疫沉淀下来。此外,在体外培养的海马神经元中,用免疫荧光染色的方法发现红色荧光标记的LIMK1与绿色荧光标记的TrkB存在部分重叠。
1.2BDNF短时间刺激体外培养的海马神经元可以引起LIMK1磷酸化、二聚化及胞内分布情况的变化
在体外培养的海马神经元的培养液中加入BDNF刺激30分钟,收集细胞裂解液,通过蛋白免疫印迹的方法检测到p-LIMK1(?)曾加。在收集的蛋白裂解液中用不含p巯基乙醇和二巯基苏糖醇的上样缓冲液98℃加热,防止破坏二硫键,BDNF刺激后可以出现LIMK1的二聚化。此外,分别抽提胞浆成分和胞膜成分,BDNF刺激30分钟引起胞浆中的LIMK1降低,胞膜中LIMK1水平升高。
1.3TrkB蛋白JM区域中的9个氨基酸介导与LIMK1蛋白的结合
将TrkB蛋白的胞内域进行逐步缺失突变,发现缺失C末端(ACT)、缺失激酶区(ATK)后,TrkB仍能与LIMK1结合,但是进一步缺失近膜区即胞内域全部缺失(JM0)后,则不能与LIMK1结合。然后将JM区域细分成5个小片段,仍然采用逐步缺失突变的方法,发现JM5、JM4能和LIMK1结合,而JM3、JM2、JM1及JM0不能与LIMK1结合,因此JM4与JM3之间的差别序列(VIENPQYFG)为介导TrkB与LIMK1结合的关键序列。此外,我们将这9个氨基酸嫁接到T1蛋白上,发现原本不能与LIMK1结合的T1也可以与LIMK1结合。
1.4干扰TrkB与LIMK1的结合抑制BDNF引起的LIMK1的磷酸化、二聚化及胞内分布的变化
将筛选出的介导TrkB与LIMK1结合的氨基酸序列嫁接到穿膜肽Tat上(Tat-JMBox4),发现该融合肽能成功的进入神经细胞内,并能有效抑制TrkB与LIMK1的相互结合。用该人工合成的短肽封闭TrkB与LIMK1的相互作用后,发现BDNF引起的LIMK1的磷酸化、二聚化及胞内分布变化的现象被抑制。
1.5BDNF长时间刺激可以延缓LIMK1的降解
在体外培养的海马神经元的培养液中,加入BDNF分别刺激1、5、15、20h后收集裂解液,发现LIMK1的蛋白水平升高。如果在加入BDNF之前,提前加入蛋白合成抑制剂放线菌酮(cycloheximide),发现加入BDNF组比不加BDNF组,LIMK1的半衰期延长,而用Tat-JMBox4干扰TrkB与LIMK1的相互作用后,BDNF对LIMK1的稳定作用被抑制。
1.6BDNF诱导轴突生长依赖于TrkB与LIMK1的相互作用
在体外培养的海马神经元中过表达LIMK1或者用小干扰RNA (siRNA)干扰LIMK1的表达,然后再用BDNF刺激,发现过表达LIMK1组神经元轴突快速生长,而干扰LIMK1表达后,BDNF促进轴突生长的作用被抑制。而且,用Tat-JMBox4抑制TrkB与LIMK1相互作用后,BDNF诱导轴突生长的功能被抑制。
2. LIMK1/cofilin信号通路调控条件性厌恶记忆消退的机制研究
2.1CTA记忆消退过程IrL脑区中cofilin活性增高
消退测试第一天(E1-)不同时间点取脑组织进行检测,发现p-cofilin在测试后0.5h和2h明显升高。第三天消退测试(E3)后0.5h与第一天进行对比,发现p-cofilin明显降低,即cofilin活性增高。
2.2CTA记忆消退过程中p-LIMK1和p-SSH1水平均降低
消退第三天(E3)p-LIMK1和p-SSH1水平比消退第一天(E1)明显降低,即在CTA记忆消退过程中LIMK1活性降低而SSH1活性升高。
2.3药物千预cofilin活性影响CTA记忆的消退进程
在前三次记忆消退测试后,在IrL脑区立即注射Tat-Ser3增加cofilin活性可以加速CTA记忆消退,而注射Tat-pSer3降低cofilin活性则阻碍CTA记忆消退。然而,在前三次记忆消退后4h,在IrL脑区中给予这两种药物均对CTA记忆消退没有影响。
2.4CTA记忆消退过程中突触体及其膜表面AMPA受体含量增加
在CTA记忆消退过程中,IrL脑区的突触体及其膜表面GluA1和GluA2的含量显著升高,而GluA3、GluA4及NR-1则没有明显变化。但是,CTA记忆消退过程中,IrL脑区总的脑组织裂解液中GluAl和GluA2的含量没有变化。
2.5药物干预cofilin活性影响突触后AMPA受体水平
在CTA记忆消退的前三天,用Tat-Ser3增加cofilin活性,可以引起GluA1和GluA2在突触体膜表面的含量,而用Tat-pSer3抑制cofilin活性则显著降低了GluA1和GluA2在突触体膜表面的含量。
2.6CTA记忆消退过程中突触形态结构没有明显变化
在CTA记忆消退过程中,树突棘头颈比(head/neck ratio)及树突棘的密度均未发生明显的变化,即使用Tat短肽干扰cofilin的活性也对树突棘的形态及密度没有影响。
2.7GluA2上膜抑制剂阻碍CTA记忆的消退
在CTA记忆消退前三天给予GluA2上膜的抑制剂(Tat-pepR845A),或者在给予Tat-Ser3增加cofilin活性的同时给予GluA2上膜的抑制剂,发现CTA记忆消退进程减慢。
结论
1. BDNF引起LIMK1蛋白发生磷酸化、二聚化及胞内重新分布的现象依赖于TrkB与LIMK1的相互作用,LIMK1蛋白的二聚化使LIMK1蛋白稳定性增加,活性增强,通过磷酸化cofilin蛋白促进肌动蛋白的聚合,从而促进轴突的生长。
2.记忆消退过程中激酶LIMK1蛋白和磷酸酶SSH1蛋白的协同作用,使得cofilin蛋白活性增强,虽然cofilin蛋白活性的增加没有引起树突棘的大小和密度发生变化,但是cofilin蛋白活性的增高促进了AMPA受体向突触体及膜表面转运,引起突触后传递效率增加,从而加速了记忆消退进程。
创新点
1. LIMK1/cofilin信号通路调控BDNF诱导的轴突生长的机制研究
1.1研究发现了一种能与TrkB蛋白相互作用的新分子即LIMK1蛋白,并且找出了TrkB分子中与LIMK1相结合的具体的氨基酸序列。
1.2发现BDNF刺激海马神经元对LIMK1存在两种不同的影响,即短时间作用可促进LIMK1活性增加并引起LIMK1在胞内重新分布,长时间刺激可稳定LIMK1蛋白延缓其降解。
1.3研究发现BDNF诱导的轴突的生长依赖于TrkB蛋白与LIMK1蛋白的相互作用。
2LIMK1/cofilin信号通路调控条件性厌恶记忆消退的机制研究
2.1发现了cofilin调控记忆消退的具体分子机制。
2.2研究发现突触传递效率的可塑性与突触形态结构的可塑性两者没有直接的相关性。
Background
Actin is a cytoskeletal protein, which plays important roles in cell physiological functions such as cytokinesis, endocytosis, neurite extension and synaptic plasticity. Actin exerting its physiological function depends on actin remodeling, that is dynamic changes of globular actin (G-actin) and filamentous actin (F-actin). Actin remodeling is regulated by many proteins including ADF/cofilin, Arp2/3, Eps8, Profilin, myosin Ⅱ and myosin Ⅴ. Since ADF/cofilin is ubiquitously expressed in eukaryote, directly regulating actin remodeling and is essential for growth and development, it is gradually becoming research focus in the fields of tumor metastasis, diseases of reproductive system, diseases of circulatory system and disorder of nervous system.
Neurons play physiological functions requiring properly growth and differentiation. The outgrowth of axons is earlier than dendrites. The terminal enlargement of axon is growth cone, composing filopodia and lamellipodia. Growth cone is rich of actin network especially beneath the membrane. Actin dynamic is the basis of neurite extension. Neurotrophins especially the most studied BDNF are important for neuronal growth, differentiation, survival and synaptic plasticity. However, the exact mechanism for BDNF promoting neurite outgrowth is pending further study.
In the central nervous system (CNS) in adults, the vast majority of neurons form a complex network in the form of chemical synapse interconnection. Chemical synapses, which are specialized junctions between axonal terminals and dendritic spines, have synaptic plasticity. Synaptic plasticity is the ability of synapse to change in strength responding to either use or disuse of transmission over synaptic pathways. Synaptic plasticity results from the alteration of neurotransmitter release, the number of receptors located on synapse and the morphology of dendritic spines. Actin dynamics is not only the basis of synaptic morphology but also closely linked to postsynaptic AMPA receptor endocytosis and insertion. Actin dynamics, which directly modulates synaptic transmission efficiency including LTP and LID, is the foundation of learning and memory. Although cofilin is the key molecule in regulating actin reorganization, the specific mechanism for cofilin regulating learning and memory remains unclear.
Objective
1. To explore the relationship between LIMK1/cofilin signaling pathway and BDNF/TrkB signaling pathway, and identify the molecular mechanism for BDNF induced axonal elongation. So that it provides the theory basis for deeply researching the therapy of BDNF mutant induced abnormalities in the nervous system.
2. To study the effect of LIMK1/cofilin signaling pathway on aversive memory extinction, and provide the theory basis for searching a potential treatment strategy for memory disorders.
Methods
1. The mechanism for LIMK1/cofilin signaling pathway regulating BDNF induced axonal elongation
1.1Detection of interaction between LIMK1and TrkB
48h after electroporation with HA-LIMK1and Flag-TrkB, HEK293cells were lysed and collected for co-immunoprecipitation and immunoblotting. We performed immunostaining experiments to compare the subcellular distribution of LIMK1and TrkB.
1.2The short term effect of BDNF on LIMK1
After serum starvation, cultured neurons were stimulated with BDNF for30min. cell lysates were collected for SDS-PAGE to detect phosphorylation of LIMK1. Cell extracts were subjected to SDS-PAGE in the absence or presence of dithiothreitol, and then immunoblotted with anti-LIMK1to test homo-dimerization level of LIMK1. Additionally, neuron lysates were separated into membrane and cytosol fraction to examine the distribution of LIMK1before and after BDNF treatment.
1.3Sequence analysis of TrkB/LIMK1interaction
Various sequences were gradually deleted from the full-length of TrkB (TrkB-FL), and co-immunoprecipitation was carried out between TrkB mutants and LIMK1. The responsible sequence for TrkB/LIMK1interaction was linked to T1protein which could not associate with LIMK1. Then we detected the interaction between chimeric receptor and LIMK1.
1.4Design the specific inhibitor for TrkB/LIMK1interaction
Based on our previous TrkB/LIMK1interaction domain mapping study, we used a synthesized peptide consisting of the9-amino acid sequence of JMBox4in TrkB fused to the membrane permeability peptide-Tat. We examined the membrane permeability by immunostaining and tested the interfering efficiency by co-immunoprecipitation endogenously and exogenously.
1.5The long term effect of BDNF on LIMK1
We detected the LIMK1level after5-20h BDNF treatment. To determine whether BDNF has an influence on LIMK1stability, we analyzed the degradation rate of the LIMK1protein in primary cultured hippocampal neurons pretreated with cycloheximide (CHX).
1.6Effect of Tat-JMBox4on BDNF induced axonal elongation
To identify the importance of LIMK1in BDNF induced axonal elongation, we tested the effect of BDNF on axonal length of the cultured neurons that were transfected with HA-LIMK1or LIMK1siRNA, respectively. Then we examined the effect of BDNF on axonal length of neurons when TrkB/LIMK1interplay was blocked by Tat-JMBox4. In addition, we detected the level of p-LIMK1, p-cofilin and F-actin in growth cone before and after BDNF treatment.
2. The mechanism for LIMK1/cofilin signaling pathway regulating aversive memory extinction
2.1Establish the experimental model and test cofilin activity
We established the CTA model and recorded the aversive index (AI). We collected different brain regions at vary times, and detected cofilin activity by Western Blot analysis. We tested phosphorylation of LIMK1and SSH1as well.
2.2The behavior change after Tat-peptide treatment
We used synthetic peptides to alter cofilin activity or inhibit GluA2synaptic insertion. Specifically Tat-Ser3can enhance cofilin activity, Tat-pSer3can weaken cofilin activity and Tat-pepR845A can block GluA2synaptic insertion. We examined the behavior change after microinjection of drugs.
2.3Expression level of AMPARs in synapse and postsynaptic membrane
We isolated crude particulate fraction of synapse termed synaptoneurosome (SNS) from the IrL, part of SNS was surface biotinylated and subsequently precipitated with neutravidin-agarose conjugate. All subunits of AMPA receptors (AMPARs) and NR1subunit of NMDA receptor were detected by immunoblotting.
2.4Morphological changes of synapse
We carried out Golgi staining to observe the structure changes including ratios of spine's head to neck and spine density.
Results
1. The mechanism for LIMK1/cofilin signaling pathway regulating BDNF induced axonal elongation
1.1LIMK1interacts with TrkB receptor
LIMK1associates with TrkB receptor endogenously and exogenously. In addition, LIMK1co-localizes with the TrkB receptor in cultured hippocampal neurons.
1.2Short term treatment of BDNF induces LIMK1phosphorylation, homo-dimerization and redistribution
30min after BDNF treatment, phosphorylation (Thr-508) of LIMK1was increased in a TrkB tyrosine kinase activity-dependent manner. BDNF induced LIMK1homo-dimerization independent of TrkB receptor tyrosine kinase activity. Additionally, BDNF stimuli increased membrane-associated LIMK1and decreased cytosolic LIMK1.
1.3JMBox4region in TrkB is responsible for TrkB/LIMK1interaction
We found that JMBox4region which is the9-amino acid sequence between JM3and JM4is necessary and sufficient for TrkB/LIMK1interaction.
1.4The short term effect of BDNF on LIMK1is dependent on TrkB/LIMK1interaction
The synthesized peptide (Tat-JMBox4) which could efficiently block TrkB/LIMK1interaction disrupted BDNF induced LIMK1phosphorylation, homo-dimerization and redistribution.
1.5Long term treatment of BDNF stabilizes LIMK1protein
We found that endogenous LIMK1was gradually degraded with a half-life of～20h when CHX was present. However, when treated with BDNF, the half-life of LIMK1protein was prolonged to>20h. The effect of BDNF on LIMK1degradation was also blocked by Tat-JMBox4.
1.7TrkB/LIMK1interaction is required for BDNF induced axonal growth
We found that up-regulation of LIMK1levels increase axonal length whereas siRNA knocking down LIMK1levels decreased axonal length. Neurons over-expressing LIMK1displayed significantly longer axon in the presence of BDNF, whereas neurons transfected with LIMK1siRNA lost their responsiveness to BDNF. Moreover, we found that the BDNF induced axonal extension was blocked by Tat-JMBox4treatment.
2. The mechanism for LIMK1/cofilin signaling pathway regulating aversive memory extinction
2.1CTA consecutive extinction training enhances cofilin activity in the IrL
We observe that the rats exhibited a transient increase in cofilin phosphorylation at30min and120min after E1, peaking at30min and returning to baseline at240min. Hence, we selected the time point30min after extinction training for measuring the p-cofilin during CTA extinction. Immunoblotting analysis showed that the p-cofilin levels were markedly reduced after E3when compared with E1.
2.2LIMK1and SSH1coordinate to regulate cofilin activity during extinction
Since LIMK1is activated by its Thr508phosphorylation and SSH1is inactivated by its Ser978phosphorylation, we used specific antibodies to determine the activity changes of LIMK1and SSH1. We observed that extinction training decreased LIMK1activity whereas increased SSH1activity.
2.3Cofilin activity is required for CTA extinction
Compared with Tat control, Tat-S3microinfusion immediately after extinction training significantly facilitated memory extinction, while Tat-pS3had the opposite effect. However, we observed that administration of Tat-Ser3or Tat-pSer3peptide into the IrL4h after E1-E3had no effect on memory extinction.
2.4Memory extinction facilitates GluAl and GluA2synaptic trafficking in the IrL
The levels of GluAl and GluA2in the SNS fraction were notably increased, whereas the level of GluA3, GluA4and NR1were not significantly changed during memory extinction. In a crude homogenized IrL fraction, the expression levels of GluAl and GluA2were unchanged. We also observed an increase in the surface levels of GluA1and GluA2subunits but no other subunits extinction.2.5cofilin activity regulates GluAl and GluA2synaptic trafficking during memory extinction We found that Tat-Ser3infusion immediately after exposure to E1-E3significantly increased the surface levels of GluA1and GluA2. On the contrary, Tat-pSer3injection decreased not only synaptic but also postsynaptic surface levels of GluAl and GluA2during memory extinction.
2.6Morphology of synapse is unchanged during memory extinction
Neither the three consecutive extinction training nor the additional regulation of cofilin activity by Tat-Ser3or Tat-pSer3could change the ratios of spine's head to neck and spine density during memory extinction.
2.7Inhibition of GluA2membrane insertion leads to memory extinction impairment
We observed that microinjection of Tat-pepR845A which could inhibit GluA2-containing AMPA receptors synaptic membrane recruitment impaired memory extinction, even when we combined the microinfusion of Tat-pepR845A and Tat-Ser3.
Conclusion
1. Our study revealed that TrkB interacted with LIMK1via its JMBox4region. BDNF induced LIMK1dimerization and phosphorylation depended on TrkB/LIMKl interaction but not TrkB tyrosine kinase activity. Furthermore, we found that BDNF induced LIMK1dimerization and transactivation played an essential role in BDNF enhanced actin polymerization and axonal elongation. These findings provide insights into the mechanistic link between LIMK1regulated actin dynamic and BDNF induced axonal elongation.
2. In this study, we found memory extinction induced a temporal activation of cofilin, which stimulated GluA1and GluA2translocation to synapse and recruitment to postsynaptic membrane. Manipulating cofilin activity could alter extinction process, which was mediated by AMPARs synaptic trafficking. Finally we showed extinction triggered modifications of synaptic physiology and spine morphology are independent processes. Understanding the actin dynamics regulated relationship between synaptic physiological function (number of synaptic receptors) and spine structure (spine size and density) is crucial to our comprehension of mechanism of memory process.
Innovation
1. The mechanism for LIMK1/cofilin signaling pathway regulating BDNF induced axonal elongation
1.1We found LIMK1could associate with TrkB receptor for the first time.
1.2Our research showed that BDNF has short term effect and long term effect on LIMK1differently.
1.3This study revealed new mechanism for BDNF induced axonal elongation.
2. The mechanism for LIMK1/cofilin signaling pathway regulating aversive memory extinction
2.1Deeply explore the molecular mechanism for LIMK1/cofilin signaling pathway regulating memory extinction.
2.2We found that synaptic physiology and spine morphology are independent processes.
引文
Allen PG (2003) Actin filament uncapping localizes to ruffling lamellae and rocketing vesicles. Nat Cell Biol 5:972-979.
Baas PW, Buster DW (2004) Slow axonal transport and the genesis of neuronal morphology. J Neurobiol 58:3-17.
Bakin AV, Safina A, Rinehart C, Daroqui C, Darbary H, Helfman DM (2004) A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 15:4682-4694.
Barkalow KL, Italiano JE, Jr., Chou DE, Matsuoka Y, Bennett V, Hartwig JH (2003) Alpha-adducin dissociates from F-actin and spectrin during platelet activation. J Cell Biol 161:557-570.
Barzik M, Kotova TI, Higgs HN, Hazelwood L, Hanein D, Gertler FB, Schafer DA (2005) Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins. J Biol Chem 280:28653-28662.
Bernstein BW, Bamburg JR (2010) ADF/Cofilin:a functional node in cell biology. Trends Cell Biol 20:187-195.
Bi AL, Wang Y, Li BQ, Wang QQ, Ma L, Yu H, Zhao L, Chen ZY (2010) Region-specific involvement of actin rearrangement-related synaptic structure alterations in conditioned taste aversion memory. Learn Mem 17:420-427.
Bradke F, Dotti CG (1999) The role of local actin instability in axon formation. Science 283:1931-1934.
Bradke F, Dotti CG (2000) Establishment of neuronal polarity:lessons from cultured hippocampal neurons. Curr Opin Neurobiol 10:574-581.
Broderick MJ, Winder SJ (2005) Spectrin, alpha-actinin, and dystrophin. Adv Protein Chem 70:203-246.
Bubb MR, Yarmola EG, Gibson BG, Southwick FS (2003) Depolymerization of actin filaments by profilin. Effects of profilin on capping protein function. J Biol Chem 278:24629-24635.
Cosker KE, Shadan S, van Diepen M, Morgan C, Li M, Allen-Baume V, Hobbs C, Doherty P, Cockcroft S, Eickholt BJ (2008) Regulation of PI3K. signalling by the phosphatidylinositol transfer protein PITPalpha during axonal extension in hippocampal neurons. J Cell Sci 121:796-803.
DesMarais V, Ghosh M, Eddy R, Condeelis J (2005) Cofilin takes the lead. J Cell Sci 118:19-26.
Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G (2004) Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol 6:1180-1188.
Dormann D, Weijer CJ (2006) Chemotactic cell movement during Dictyostelium development and gastrulation. Curr Opin Genet Dev 16:367-373.
Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI (2005) Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123:903-915.
During RL, Li W, Hao B, Koenig JM, Stephens DS, Quinn CP, Southwick FS (2005) Anthrax lethal toxin paralyzes neutrophil actin-based motility. J Infect Dis 192:837-845.
Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P (2005) The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem J 389:127-135.
Fass J, Gehler S, Sarmiere P, Letourneau P, Bamburg JR (2004) Regulating filopodial dynamics through actin-depolymerizing factor/cofilin. Anat Sci Int 79:173-183.
Feng Y, Walsh CA (2004) The many faces of filamin:a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034-1038.
Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2004) Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear. J Neurosci 24:1962-1966.
Fischer RS, Fowler VM (2003) Tropomodulins:life at the slow end. Trends Cell Biol 13:593-601.
Forscher P, Smith SJ (1988) Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J Cell Biol 107:1505-1516.
Fukata Y, Kimura T, Kaibuchi K (2002) Axon specification in hippocampal neurons. Neurosci Res 43:305-315.
Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38:447-460.
Gardel ML, Nakamura F, Hartwig JH, Crocker JC, Stossel TP, Weitz DA (2006) Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc Natl Acad Sci U S A 103:1762-1767.
Gardel ML, Shin JH, MacKintosh FC, Mahadevan L, Matsudaira P, Weitz DA (2004) Elastic behavior of cross-linked and bundled actin networks. Science 304:1301-1305.
Gouin E, Welch MD, Cossart P (2005) Actin-based motility of intracellular pathogens. Curr Opin Microbiol 8:35-45.
Grummt I (2006) Actin and myosin as transcription factors. Curr Opin Genet Dev 16:191-196.
Hering H, Sheng M (2003) Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J Neurosci 23:11759-11769.
Higgs HN (2005) Formin proteins:a domain-based approach. Trends Biochem Sci 30:342-353.
Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H (2008) The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57:719-729.
Hou YY, Lu B, Li M, Liu Y, Chen J, Chi ZQ, Liu JG (2009) Involvement of actin rearrangements within the amygdala and the dorsal hippocampus in aversive memories of drug withdrawal in acute morphine-dependent rats. J Neurosci 29:12244-12254.
Iki J, Inoue A, Bito H, Okabe S (2005) Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur J Neurosci 22:2985-2994.
Kumar N, Tomar A, Parrill AL, Khurana S (2004) Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J Biol Chem 279:45036-45046.
Landsverk ML, Epstein HF (2005) Genetic analysis of myosin II assembly and organization in model organisms. Cell Mol Life Sci 62:2270-2282.
Linder S, Kopp P (2005) Podosomes at a glance. J Cell Sci 118:2079-2082.
Littlefield R, Almenar-Queralt A, Fowler VM (2001) Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nat Cell Biol 3:544-551.
Lua BL, Low BC (2005) Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett 579:577-585.
Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774-3786.
Mirzapoiazova T, Kolosova IA, Romer L, Garcia JG, Verin AD (2005) The role of caldesmon in the regulation of endothelial cytoskeleton and migration. J Cell Physiol 203:520-528.
Mitchison TJ, Cramer LP (1996) Actin-based cell motility and cell locomotion. Cell 84:371-379.
Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Racl and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-10449.
Mizui T, Takahashi H, Sekino Y, Shirao T (2005) Overexpression of drebrin A in immature neurons induces the accumulation of F-actin and PSD-95 into dendritic filopodia, and the formation of large abnormal protrusions. Mol Cell Neurosci 30:630-638.
Motanis H, Maroun M (2012) Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning. Hippocampus 22:494-500.
Nakamura F, Osborn E, Janmey PA, Stossel TP (2002) Comparison of filamin A-induced cross-linking and Arp2/3 complex-mediated branching on the mechanics of actin filaments. J Biol Chem 277:9148-9154.
Nicholson-Dykstra S, Higgs HN, Harris ES (2005) Actin dynamics:growth from dendritic branches. Curr Biol 15:R346-357.
Niggli V (2005) Regulation of protein activities by phosphoinositide phosphates. Annu Rev Cell Dev Biol 21:57-79.
Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE, Huganir RL (2003) Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37:263-274.
Rafelski SM, Theriot JA (2004) Crawling toward a unified model of cell mobility:spatial and temporal regulation of actin dynamics. Annu Rev Biochem 73:209-239.
Rehberg K, Bergado-Acosta JR, Koch JC, Stork O (2010) Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala. Neurobiol Learn Mem 94:117-126.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-3029.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283-289.
Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7:923-929.
Stradal TE, Scita G (2006) Protein complexes regulating Arp2/3-mediated actin assembly. Curr Opin Cell Biol 18:4-10.
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683-1687.
Toda S, Shen HW, Peters J, Cagle S, Kalivas PW (2006) Cocaine increases actin cycling:effects in the reinstatement model of drug seeking. J Neurosci 26:1579-1587.
Tyler WJ, Pozzo-Miller LD (2001) BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 21:4249-4258.
Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118:4917-4919.
Yang C, Pring M, Wear MA, Huang M, Cooper JA, Svitkina TM, Zigmond SH (2005) Mammalian CARMIL inhibits actin filament capping by capping protein. Dev Cell 9:209-221.
Yarmola EG, Bubb MR (2004) Effects of profilin and thymosin beta4 on the critical concentration of actin demonstrated in vitro and in cell extracts with a novel direct assay. J Biol Chem 279:33519-33527.
Yin HL, Janmey PA (2003) Phosphoinositide regulation of the actin cytoskeleton. Annu Rev Physiol 65:761-789.
Yoshimura T, Arimura N, Kaibuchi K (2006) Signaling networks in neuronal polarization. J Neurosci 26:10626-10630.
Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF (2005) A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 25:3379-3388.
Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68.
Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R (2006) LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer 118:2703-2710.
Bartkowska K, Turlejski K, Djavadian RL (2010) Neurotrophins and their receptors in early development of the mammalian nervous system. Acta Neurobiol Exp (Wars) 70:454-467.
Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell B 39:1071-1076.
Bernard O, Ganiatsas S, Kannourakis G, Dringen R (1994) Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ 5:1159-1171.
Birkenfeld J, Betz H, Roth D (2001) Inhibition of neurite extension by overexpression of individual domains of LIM kinase 1. J Neurochem 78:924-927.
Buchan AM, Lin CY, Choi J, Barber DL (2002) Somatostatin, acting at receptor subtype 1, inhibits Rho activity, the assembly of actin stress fibers, and cell migration. J Biol Chem 277:28431-28438.
Chao MV (2003) Neurotrophins and their receptors:a convergence point for many signalling pathways. Nat Rev Neurosci 4:299-309.
Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM (2011) Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci U S A 108:18430-18435.
Claus C, Chey S, Heinrich S, Reins M, Richardt B, Pinkert S, Fechner H, Gaunitz F, Schafer I, Seibel P, Liebert UG (2011) Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus. Journal of Virology 85:3881-3892.
Cosker KE, Shadan S, van Diepen M, Morgan C, Li M, Allen-Baume V, Hobbs C, Doherty P, Cockcroft S, Eickholt BJ (2008) Regulation of PI3K signalling by the phosphatidylinositol transfer protein PITPalpha during axonal extension in hippocampal neurons. J Cell Sci 121:796-803.
Cunha C, Brambilla R, Thomas KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3:1.
Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754-9763.
Endo M, Ohashi K, Mizuno K (2007) LIM kinase and slingshot are critical for neurite extension. J Biol Chem 282:13692-13702.
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527-2537.
Gehler S, Gallo G, Veien E, Letourneau PC (2004) p75 neurotrophin receptor signaling regulates growth cone filopodial dynamics through modulating RhoA activity. J Neurosci 24:4363-4372.
Goldberg JL (2003) How does an axon grow? Genes Dev 17:941-958.
Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA (2002) Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 33:689-702.
Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1-49.
Heitz F, Morris MC, Divita G (2009) Twenty years of cell-penetrating peptides:from molecular mechanisms to therapeutics. Br J Pharmacol 157:195-206.
Horita Y, Ohashi K, Mukai M, Inoue M, Mizuno K (2008) Suppression of the invasive capacity of rat ascites hepatoma cells by knockdown of Slingshot or LIM kinase. J Biol Chem 283:6013-6021.
Labelle C, Leclerc N (2000) Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons. Brain Res Dev Brain Res 123:1-11.
Li R, Soosairajah J, Harari D, Citri A, Price J, Ng HL, Morton CJ, Parker MW, Yarden Y, Bernard O (2006) Hsp90 increases LIM kinase activity by promoting its homo-dimerization. Faseb J 20:1218-1220.
Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86-98.
Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774-3786.
Matsui S, Matsumoto S, Adachi R, Kusui K, Hirayama A, Watanabe H, Ohashi K, Mizuno K, Yamaguchi T, Kasahara T, Suzuki K (2002) LIM kinase 1 modulates opsonized zymosan-triggered activation of macrophage-like U937 cells. Possible involvement of phosphorylation of cofilin and reorganization of actin cytoskeleton. J Biol Chem 277:544-549.
Meng YH, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jial ZP (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121-133.
Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401-414.
Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiaml, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-10449.
Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T (2010) Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc Natl Acad Sci U S A 107:7586-7591.
Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K (2006) A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol 126:627-638.
Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7:276-285.
Proschel C, Blouin MJ, Gutowski NJ, Ludwig R, Noble M (1995) Limkl is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro. Oncogene 11:1271-1281.
Purcell AL, Carew TJ (2003) Tyrosine kinases, synaptic plasticity and memory:insights from vertebrates and invertebrates. Trends Neurosci 26:625-630.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-3029.
Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T, Quiroga S, Ferreira A, Caceres A (2004) LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell 15:3433-3449.
Santos AR, Comprido D, Duarte CB (2010) Regulation of local translation at the synapse by BDNF. Prog Neurobiol 92:505-516.
Schecterson LC, Bothwell M (2010) Neurotrophin Receptors:Old Friends with New Partners. Developmental Neurobiology 70:332-338.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283-289.
Scott RW, Olson MF (2007) LIM kinases:function, regulation and association with human disease. J Mol Med (Berl) 85:555-568.
Shen K, Cowan CW (2010) Guidance molecules in synapse formation and plasticity. Cold Spring Harb Perspect Biol 2:a001842.
Tahirovic S, Bradke F (2009) Neuronal polarity. Cold Spring Harb Perspect Biol 1:a001644.
Takahashi H, Koshimizu U, Nakamura T (1998) A novel transcript encoding truncated LIM kinase 2 is specifically expressed in male germ cells undergoing meiosis. Biochem Biophys Res Commun 249:138-145.
Toda S, Shen HW, Peters J, Cagle S, Kalivas PW (2006) Cocaine increases actin cycling:effects in the reinstatement model of drug seeking. Journal of Neuroscience 26:1579-1587.
Tucker KL (2002) Neurotrophins and the control of axonal outgrowth. Panminerva Med 44:325-333.
Tursun B, Schluter A, Peters MA, Viehweger B, Ostendorff HP, Soosairajah J, Drung A, Bossenz M, Johnsen SA, Schweizer M, Bernard O, Bach I (2005) The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 19:2307-2319.
Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation:on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224-237.
Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137-149.
Zhao L, Sheng AL, Huang SH, Yin YX, Chen B, Li XZ, Zhang Y, Chen ZY (2009) Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface. J Cell Sci 122:3123-3136.
Agnew BJ, Minamide LS, Bamburg JR (1995) Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site. J Biol Chem 270:17582-17587.
Aizawa H, Wakatsuki S, Ishii A, Moriyama K, Sasaki Y, Ohashi K, Sekine-Aizawa Y, Sehara-Fujisawa A, Mizuno K, Goshima Y, Yahara I (2001) Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nat Neurosci 4:367-373.
Allen PG (2003) Actin filament uncapping localizes to ruffling lamellae and rocketing vesicles. Nat Cell Biol 5:972-979.
Anggono V, Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 22:461-469.
Aunis D, Bader MF (1988) The cytoskeleton as a barrier to exocytosis in secretory cells. J Exp Biol 139:253-266.
Baas PW, Buster DW (2004) Slow axonal transport and the genesis of neuronal morphology. J Neurobiol 58:3-17.
Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R (2006) LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer 118:2703-2710.
Bakin AV, Safina A, Rinehart C, Daroqui C, Darbary H, Helfman DM (2004) A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 15:4682-4694.
Bamburg JR (1999) Proteins of the ADF/cofilin family:essential regulators of actin dynamics. Annu Rev Cell Dev Biol 15:185-230.
Barkalow KL, Italiano JE, Jr., Chou DE, Matsuoka Y, Bennett V, Hartwig JH (2003) Alpha-adducin dissociates from F-actin and spectrin during platelet activation. J Cell Biol 161:557-570.
Barrett D, Shumake J, Jones D, Gonzalez-Lima F (2003) Metabolic mapping of mouse brain activity after extinction of a conditioned emotional response. J Neurosci 23:5740-5749.
Bartkowska K, Turlejski K, Djavadian RL (2010) Neurotrophins and their receptors in early development of the mammalian nervous system. Acta Neurobiol Exp (Wars) 70:454-467.
Barzik M, Kotova TI, Higgs HN, Hazelwood L, Hanein D, Gertler FB, Schafer DA (2005) Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins. J Biol Chem 280:28653-28662.
Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell B 39:1071-1076.
Bernard O, Ganiatsas S, Kannourakis G, Dringen R (1994) Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ 5:1159-1171.
Bernstein BW, Bamburg JR (2010a) ADF/Cofilin:a functional node in cell biology. Trends Cell Biol 20:187-195.
Bernstein BW, Bamburg JR (2010b) ADF/cofilin:a functional node in cell biology. Trends Cell Biol 20:187-195.
Bi AL, Wang Y, Li BQ, Wang QQ, Ma L, Yu H, Zhao L, Chen ZY (2010) Region-specific involvement of actin rearrangement-related synaptic structure alterations in conditioned taste aversion memory. Learn Mem 17:420-427.
Birkenfeld J, Betz H, Roth D (2001) Inhibition of neurite extension by overexpression of individual domains of LIM kinase 1. J Neurochem 78:924-927.
Bradke F, Dotti CG (1999) The role of local actin instability in axon formation. Science 283:1931-1934.
Bradke F, Dotti CG (2000) Establishment of neuronal polarity:lessons from cultured hippocampal neurons. Curr Opin Neurobiol 10:574-581.
Bramham CR (2008) Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol 18:524-531.
Broderick MJ, Winder SJ (2005) Spectrin, alpha-actinin, and dystrophin. Adv Protein Chem 70:203-246.
Bubb MR, Yarmola EG, Gibson BG, Southwick FS (2003) Depolymerization of actin filaments by profilin. Effects of profilin on capping protein function. J Biol Chem 278:24629-24635.
Buchan AM, Lin CY, Choi J, Barber DL (2002) Somatostatin, acting at receptor subtype 1, inhibits Rho activity, the assembly of actin stress fibers, and cell migration. J Biol Chem 277:28431-28438.
Carlisle HJ, Kennedy MB (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182-187.
Carlisle HJ, Manzerra P, Marcora E, Kennedy MB (2008) SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J Neurosci 28:13673-13683.
Chao MV (2003) Neurotrophins and their receptors:a convergence point for many signalling pathways. Nat Rev Neurosci 4:299-309.
Chen LY, Rex CS, Casale MS, Gall CM, Lynch G (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci 27:5363-5372.
Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM (2011) Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci U S A 108:18430-18435.
Cingolani LA, Goda Y (2008) Actin in action:the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9:344-356.
Claus C, Chey S, Heinrich S, Reins M, Richardt B, Pinkert S, Fechner H, Gaunitz F, Schafer I, Seibel P, Liebert UG (2011) Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus. Journal of Virology 85:3881-3892.
Cosker KE, Shadan S, van Diepen M, Morgan C, Li M, Allen-Baume V, Hobbs C, Doherty P, Cockcroft S, Eickholt BJ (2008) Regulation of PI3K signalling by the phosphatidylinositol transfer protein PITPalpha during axonal extension in hippocampal neurons. J Cell Sci 121:796-803.
Cunha C, Brambilla R, Thomas KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3:1.
Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754-9763.
Davis M, Ressler K, Rothbaum BO, Richardson R (2006) Effects of D-cycloserine on extinction:translation from preclinical to clinical work. Biol Psychiatry 60:369-375.
DesMarais V, Ghosh M, Eddy R, Condeelis J (2005) Cofilin takes the lead. J Cell Sci 118:19-26.
Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G (2004) Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol 6:1180-1188.
Dormann D, Weijer CJ (2006) Chemotactic cell movement during Dictyostelium development and gastrulation. Curr Opin Genet Dev 16:367-373.
Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI (2005) Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123:903-915.
During RL, Li W, Hao B, Koenig JM, Stephens DS, Quinn CP, Southwick FS (2005) Anthrax lethal toxin paralyzes neutrophil actin-based motility. J Infect Dis 192:837-845.
Eitzen G (2003) Actin remodeling to facilitate membrane fusion. Biochim Biophys Acta 1641:175-181.
Endo M, Ohashi K, Mizuno K (2007) LIM kinase and slingshot are critical for neurite extension. J Biol Chem 282:13692-13702.
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003a) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527-2537.
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003b) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527-2537.
Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P (2005) The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem J 389:127-135.
Fass J, Gehler S, Sarmiere P, Letourneau P, Bamburg JR (2004) Regulating filopodial dynamics through actin-depolymerizing factor/cofilin. Anat Sci Int 79:173-183.
Feng Y, Walsh CA (2004) The many faces of filamin:a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034-1038.
Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825-838.
Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2004) Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear. J Neurosci 24:1962-1966.
Fischer RS, Fowler VM (2003) Tropomodulins:life at the slow end. Trends Cell Biol 13:593-601.
Forscher P, Smith SJ (1988) Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J Cell Biol 107:1505-1516.
Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexinl-dependent mechanism. Nat Neurosci 10:67-76.
Fukata Y, Kimura T, Kaibuchi K (2002) Axon specification in hippocampal neurons. Neurosci Res 43:305-315.
Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38:447-460.
Gardel ML, Nakamura F, Hartwig JH, Crocker JC, Stossel TP, Weitz DA (2006) Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc Natl Acad Sci U S A 103:1762-1767.
Gardel ML, Shin JH, MacKintosh FC, Mahadevan L, Matsudaira P, Weitz DA (2004) Elastic behavior of cross-linked and bundled actin networks. Science 304:1301-1305.
Gehler S, Gallo G, Veien E, Letourneau PC (2004) p75 neurotrophin receptor signaling regulates growth cone filopodial dynamics through modulating RhoA activity. J Neurosci 24:4363-4372.
Goldberg JL (2003) How does an axon grow? Genes Dev 17:941-958.
Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA (2002) Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 33:689-702.
Gouin E, Welch MD, Cossart P (2005) Actin-based motility of intracellular pathogens. Curr Opin Microbiol 8:35-45.
Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1-49.
Grummt I (2006) Actin and myosin as transcription factors. Curr Opin Genet Dev 16:191-196.
Gu JP, Lee CW, Fan YJ, Komlos D, Tang X, Sun CC, Yu KA, Hartzell HC, Chen G, Bamburg JR, Zheng JQ (2010) ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13:1208-1215.
. Heitz F, Morris MC, Divita G (2009) Twenty years of cell-penetrating peptides:from molecular mechanisms to therapeutics. Br J Pharmacol 157:195-206.
Hering H, Sheng M (2003) Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J Neurosci 23:11759-11769.
Higgs HN (2005) Formin proteins:a domain-based approach. Trends Biochem Sci 30:342-353.
Hollingsworth EB, McNeal ET, Burton JL, Williams RJ, Daly JW, Creveling CR (1985) Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3':5'-monophosphate-generating systems, receptors, and enzymes. J Neurosci 5:2240-2253.
Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H (2008) The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57:719-729.
Horita Y, Ohashi K, Mukai M, Inoue M, Mizuno K (2008) Suppression of the invasive capacity of rat ascites hepatoma cells by knockdown of Slingshot or LIM kinase. J Biol Chem 283:6013-6021.
Hotulainen P, Hoogenraad CC (2010) Actin in dendritic spines: connecting dynamics to function. J Cell Biol 189:619-629.
Hou YY, Lu B, Li M, Liu Y, Chen J, Chi ZQ, Liu JG (2009) Involvement of actin rearrangements within the amygdala and the dorsal hippocampus in aversive memories of drug withdrawal in acute morphine-dependent rats. J Neurosci 29:12244-12254.
Iki J, Inoue A, Bito H, Okabe S (2005) Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur J Neurosci 22:2985-2994.
Joels G, Lamprecht R (2010) Interaction between N-ethylmaleimide-sensitive factor and GluR2 is essential for fear memory formation in lateral amygdala. J Neurosci 30:15981-15986.
Kullmann DM (2003) Silent synapses:what are they telling us about long-term potentiation? Philos Trans R Soc Lond B Biol Sci 358:727-733.
Kumar N, Tomar A, Parrill AL, Khurana S (2004) Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J Biol Chem 279:45036-45046.
Labelle C, Leclerc N (2000) Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons. Brain Res Dev Brain Res 123:1-11.
Landsverk ML, Epstein HF (2005) Genetic analysis of myosin Ⅱ assembly and organization in model organisms. Cell Mol Life Sci 62:2270-2282.
Li R, Soosairajah J, Harari D, Citri A, Price J, Ng HL, Morton CJ, Parker MW, Yarden Y, Bernard O (2006) Hsp90 increases LIM kinase activity by promoting its homo-dimerization. Faseb J 20:1218-1220.
Linder S, Kopp P (2005) Podosomes at a glance. J Cell Sci 118:2079-2082.
Littlefield R, Almenar-Queralt A, Fowler VM (2001) Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nat Cell Biol 3:544-551.
Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86-98.
Lua BL, Low BC (2005) Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett 579:577-585.
Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774-3786.
Mantzur L, Joels G, Lamprecht R (2009) Actin polymerization in lateral amygdala is essential for fear memory formation. Neurobiol Learn Mem 91:85-88.
Matsui S, Matsumoto S, Adachi R, Kusui K, Hirayama A, Watanabe H, Ohashi K, Mizuno K, Yamaguchi T, Kasahara T, Suzuki K (2002) LIM kinase 1 modulates opsonized zymosan-triggered activation of macrophage-like U937 cells. Possible involvement of phosphorylation of cofilin and reorganization of actin cytoskeleton. J Biol Chem 277:544-549.
Matus A (2000) Actin-based plasticity in dendritic spines. Science 290:754-758.
Meng YH, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jial ZP (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121-133.
Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70-74.
Miller G (2004) Forgetting and remembering. Learning to forget. Science 304:34-36.
Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401-414.
Mirzapoiazova T, Kolosova IA, Romer L, Garcia JG, Verin AD (2005) The role of caldesmon in the regulation of endothelial cytoskeleton and migration. J Cell Physiol 203:520-528.
Mitchison TJ, Cramer LP (1996) Actin-based cell motility and cell locomotion. Cell 84:371-379.
Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-10449.
Mizui T, Takahashi H, Sekino Y, Shirao T (2005) Overexpression of drebrin A in immature neurons induces the accumulation of F-actin and PSD-95 into dendritic filopodia, and the formation of large abnormal protrusions. Mol Cell Neurosci 30:630-638.
Motanis H, Maroun M (2012) Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning. Hippocampus 22:494-500.
Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36:567-584.
Nakamura F, Osborn E, Janmey PA, Stossel TP (2002) Comparison of filamin A-induced cross-linking and Arp2/3 complex-mediated branching on the mechanics of actin filaments. J Biol Chem 277:9148-9154.
Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T (2010) Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc Natl Acad Sci U S A 107:7586-7591.
Nicholson-Dykstra S, Higgs HN, Harris ES (2005) Actin dynamics: growth from dendritic branches. Curr Biol 15:R346-357.
Niggli V (2005) Regulation of protein activities by phosphoinositide phosphates. Annu Rev Cell Dev Biol 21:57-79.
Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K (2006) A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol 126:627-638.
Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7:276-285.
Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates. New York:Academic.
Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE, Huganir RL (2003) Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37:263-274.
Proschel C, Blouin MJ, Gutowski NJ, Ludwig R, Noble M (1995) Limkl is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro. Oncogene 11:1271-1281.
Purcell AL, Carew TJ (2003) Tyrosine kinases, synaptic plasticity and memory:insights from vertebrates and invertebrates. Trends Neurosci 26:625-630.
Rafelski SM, Theriot JA (2004) Crawling toward a unified model of cell mobility:spatial and temporal regulation of actin dynamics. Annu Rev Biochem 73:209-239.
Rehberg K, Bergado-Acosta JR, Koch JC, Stork O (2010) Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala. Neurobiol Learn Mem 94:117-126.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-3029.
Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T, Quiroga S, Ferreira A, Caceres A (2004) LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell 15:3433-3449.
Rust MB, Gurniak CB, Renner M, Vara H, Morando L, Gorlich A, Sassoe-Pognetto M, Al Banchaabouchi M, Giustetto M, Triller A, Choquet D, Witke W (2010) Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. Embo J 29:1889-1902.
Sananbenesi F, Fischer A, Wang XY, Schrick C, Neve R, Radulovic J, Tsai LH (2007) A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci 10:1012-1019.
Santos AR, Comprido D, Duarte CB (2010) Regulation of local translation at the synapse by BDNF. Prog Neurobiol 92:505-516.
Schecterson LC, Bothwell M (2010) Neurotrophin Receptors:Old Friends with New Partners. Developmental Neurobiology 70:332-338.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283-289.
Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7:923-929.
Scott RW, Olson MF (2007) LIM kinases:function, regulation and association with human disease. J Mol Med (Berl) 85:555-568.
Shen K, Cowan CW (2010) Guidance molecules in synapse formation and plasticity. Cold Spring Harb Perspect Biol 2:a001842.
Stradal TE, Scita G (2006) Protein complexes regulating Arp2/3-mediated actin assembly. Curr Opin Cell Biol 18:4-10.
Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95-101.
Tahirovic S, Bradke F (2009) Neuronal polarity. Cold Spring Harb Perspect Biol 1:a001644.
Takahashi H, Koshimizu U, Nakamura T (1998) A novel transcript encoding truncated LIM kinase 2 is specifically expressed in male germ cells undergoing meiosis. Biochem Biophys Res Commun 249:138-145.
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683-1687.
Toda S, Shen HW, Peters J, Cagle S, Kalivas PW (2006) Cocaine increases actin cycling:effects in the reinstatement model of drug seeking. Journal of Neuroscience 26:1579-1587.
Tucker KL (2002) Neurotrophins and the control of axonal outgrowth. Panminerva Med 44:325-333.
Tursun B, Schluter A, Peters MA, Viehweger B, Ostendorff HP, Soosairajah J, Drung A, Bossenz M, Johnsen SA, Schweizer M, Bernard O, Bach I (2005) The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 19:2307-2319.
Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation:on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224-237.
Tyler WJ, Pozzo-Miller LD (2001) BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 21:4249-4258.
Van Troys M, Huyck L, Leyman S, Dhaese S, Vandekerkhove J, Ampe C (2008) Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol 87:649-667.
Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118:4917-4919.
Villasana LE, Klann E, Tejada-Simon MV (2006) Rapid isolation of synaptoneurosomes and postsynaptic densities from adult mouse hippocampus. J Neurosci Methods 158:30-36.
Yang C, Pring M, Wear MA, Huang M, Cooper JA, Svitkina TM, Zigmond SH (2005) Mammalian CARMIL inhibits actin filament capping by capping protein. Dev Cell 9:209-221.
Yao Y, Kelly MT, Sajikumar S, Serrano P, Tian D, Bergold PJ, Frey JU, Sacktor TC (2008) PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J Neurosci 28:7820-7827.
Yarmola EG, Bubb MR (2004) Effects of profilin and thymosin beta4 on the critical concentration of actin demonstrated in vitro and in cell extracts with a novel direct assay. J Biol Chem 279:33519-33527.
Yin HL, Janmey PA (2003) Phosphoinositide regulation of the actin cytoskeleton. Annu Rev Physiol 65:761-789.
Yoshimura T, Arimura N, Kaibuchi K (2006) Signaling networks in neuronal polarization. J Neurosci 26:10626-10630.
Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137-149.
Yuen EY, Liu W, Kafri T, van Praag H, Yan Z (2010) Regulation of AMPA receptor channels and synaptic plasticity by cofilin phosphatase Slingshot in cortical neurons. J Physiol 588:2361-2371.
Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF (2005) A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 25:3379-3388.
Zhao L, Sheng AL, Huang SH, Yin YX, Chen B, Li XZ, Zhang Y, Chen ZY (2009) Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface. J Cell Sci 122:3123-3136.
Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68.
Zhou Q, Xiao M, Nicoll RA (2001) Contribution of cytoskeleton to the internalization of AMPA receptors. Proc Natl Acad Sci U S A 98:1261-1266.
Zhou Z, Hu J, Passafaro M, Xie W, Jia Z (2011) GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. J Neurosci 31:819-833.
Zushida K, Sakurai M, Wada K, Sekiguchi M (2007) Facilitation of extinction learning for contextual fear memory by PEPA:a potentiator of AMPA receptors. J Neurosci 27:158-166.
Baas PW, Buster DW (2004) Slow axonal transport and the genesis of neuronal morphology. J Neurobiol 58:3-17.
Bakin AV, Safina A, Rinehart C, Daroqui C, Darbary H, Helfman DM (2004) A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 15:4682-4694.
Barkalow KL, Italiano JE, Jr., Chou DE, Matsuoka Y, Bennett V, Hartwig JH (2003) Alpha-adducin dissociates from F-actin and spectrin during platelet activation. J Cell Biol 161:557-570.
Barzik M, Kotova TI, Higgs HN, Hazelwood L, Hanein D, Gertler FB, Schafer DA (2005) Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins. J Biol Chem 280:28653-28662.
Bernstein BW, Bamburg JR (2010) ADF/Cofilin:a functional node in cell biology. Trends Cell Biol 20:187-195.
Bi AL, Wang Y, Li BQ, Wang QQ, Ma L, Yu H, Zhao L, Chen ZY (2010) Region-specific involvement of actin rearrangement-related synaptic structure alterations in conditioned taste aversion memory. Learn Mem 17:420-427.
Bradke F, Dotti CG (1999) The role of local actin instability in axon formation. Science 283:1931-1934.
Bradke F, Dotti CG (2000) Establishment of neuronal polarity:lessons from cultured hippocampal neurons. Curr Opin Neurobiol 10:574-581.
Broderick MJ, Winder SJ (2005) Spectrin, alpha-actinin, and dystrophin. Adv Protein Chem 70:203-246.
Bubb MR, Yarmola EG, Gibson BG, Southwick FS (2003) Depolymerization of actin filaments by profilin. Effects of profilin on capping protein function. J Biol Chem 278:24629-24635.
Cosker KE, Shadan S, van Diepen M, Morgan C, Li M, Allen-Baume V, Hobbs C, Doherty P, Cockcroft S, Eickholt BJ (2008) Regulation of PI3K. signalling by the phosphatidylinositol transfer protein PITPalpha during axonal extension in hippocampal neurons. J Cell Sci 121:796-803.
DesMarais V, Ghosh M, Eddy R, Condeelis J (2005) Cofilin takes the lead. J Cell Sci 118:19-26.
Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G (2004) Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol 6:1180-1188.
Dormann D, Weijer CJ (2006) Chemotactic cell movement during Dictyostelium development and gastrulation. Curr Opin Genet Dev 16:367-373.
Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI (2005) Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123:903-915.
During RL, Li W, Hao B, Koenig JM, Stephens DS, Quinn CP, Southwick FS (2005) Anthrax lethal toxin paralyzes neutrophil actin-based motility. J Infect Dis 192:837-845.
Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P (2005) The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem J 389:127-135.
Fass J, Gehler S, Sarmiere P, Letourneau P, Bamburg JR (2004) Regulating filopodial dynamics through actin-depolymerizing factor/cofilin. Anat Sci Int 79:173-183.
Feng Y, Walsh CA (2004) The many faces of filamin:a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034-1038.
Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2004) Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear. J Neurosci 24:1962-1966.
Fischer RS, Fowler VM (2003) Tropomodulins:life at the slow end. Trends Cell Biol 13:593-601.
Forscher P, Smith SJ (1988) Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J Cell Biol 107:1505-1516.
Fukata Y, Kimura T, Kaibuchi K (2002) Axon specification in hippocampal neurons. Neurosci Res 43:305-315.
Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38:447-460.
Gardel ML, Nakamura F, Hartwig JH, Crocker JC, Stossel TP, Weitz DA (2006) Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc Natl Acad Sci U S A 103:1762-1767.
Gardel ML, Shin JH, MacKintosh FC, Mahadevan L, Matsudaira P, Weitz DA (2004) Elastic behavior of cross-linked and bundled actin networks. Science 304:1301-1305.
Gouin E, Welch MD, Cossart P (2005) Actin-based motility of intracellular pathogens. Curr Opin Microbiol 8:35-45.
Grummt I (2006) Actin and myosin as transcription factors. Curr Opin Genet Dev 16:191-196.
Hering H, Sheng M (2003) Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J Neurosci 23:11759-11769.
Higgs HN (2005) Formin proteins:a domain-based approach. Trends Biochem Sci 30:342-353.
Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H (2008) The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57:719-729.
Hou YY, Lu B, Li M, Liu Y, Chen J, Chi ZQ, Liu JG (2009) Involvement of actin rearrangements within the amygdala and the dorsal hippocampus in aversive memories of drug withdrawal in acute morphine-dependent rats. J Neurosci 29:12244-12254.
Iki J, Inoue A, Bito H, Okabe S (2005) Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur J Neurosci 22:2985-2994.
Kumar N, Tomar A, Parrill AL, Khurana S (2004) Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J Biol Chem 279:45036-45046.
Landsverk ML, Epstein HF (2005) Genetic analysis of myosin II assembly and organization in model organisms. Cell Mol Life Sci 62:2270-2282.
Linder S, Kopp P (2005) Podosomes at a glance. J Cell Sci 118:2079-2082.
Littlefield R, Almenar-Queralt A, Fowler VM (2001) Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nat Cell Biol 3:544-551.
Lua BL, Low BC (2005) Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett 579:577-585.
Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774-3786.
Mirzapoiazova T, Kolosova IA, Romer L, Garcia JG, Verin AD (2005) The role of caldesmon in the regulation of endothelial cytoskeleton and migration. J Cell Physiol 203:520-528.
Mitchison TJ, Cramer LP (1996) Actin-based cell motility and cell locomotion. Cell 84:371-379.
Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Racl and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-10449.
Mizui T, Takahashi H, Sekino Y, Shirao T (2005) Overexpression of drebrin A in immature neurons induces the accumulation of F-actin and PSD-95 into dendritic filopodia, and the formation of large abnormal protrusions. Mol Cell Neurosci 30:630-638.
Motanis H, Maroun M (2012) Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning. Hippocampus 22:494-500.
Nakamura F, Osborn E, Janmey PA, Stossel TP (2002) Comparison of filamin A-induced cross-linking and Arp2/3 complex-mediated branching on the mechanics of actin filaments. J Biol Chem 277:9148-9154.
Nicholson-Dykstra S, Higgs HN, Harris ES (2005) Actin dynamics:growth from dendritic branches. Curr Biol 15:R346-357.
Niggli V (2005) Regulation of protein activities by phosphoinositide phosphates. Annu Rev Cell Dev Biol 21:57-79.
Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE, Huganir RL (2003) Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37:263-274.
Rafelski SM, Theriot JA (2004) Crawling toward a unified model of cell mobility:spatial and temporal regulation of actin dynamics. Annu Rev Biochem 73:209-239.
Rehberg K, Bergado-Acosta JR, Koch JC, Stork O (2010) Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala. Neurobiol Learn Mem 94:117-126.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-3029.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283-289.
Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7:923-929.
Stradal TE, Scita G (2006) Protein complexes regulating Arp2/3-mediated actin assembly. Curr Opin Cell Biol 18:4-10.
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683-1687.
Toda S, Shen HW, Peters J, Cagle S, Kalivas PW (2006) Cocaine increases actin cycling:effects in the reinstatement model of drug seeking. J Neurosci 26:1579-1587.
Tyler WJ, Pozzo-Miller LD (2001) BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 21:4249-4258.
Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118:4917-4919.
Yang C, Pring M, Wear MA, Huang M, Cooper JA, Svitkina TM, Zigmond SH (2005) Mammalian CARMIL inhibits actin filament capping by capping protein. Dev Cell 9:209-221.
Yarmola EG, Bubb MR (2004) Effects of profilin and thymosin beta4 on the critical concentration of actin demonstrated in vitro and in cell extracts with a novel direct assay. J Biol Chem 279:33519-33527.
Yin HL, Janmey PA (2003) Phosphoinositide regulation of the actin cytoskeleton. Annu Rev Physiol 65:761-789.
Yoshimura T, Arimura N, Kaibuchi K (2006) Signaling networks in neuronal polarization. J Neurosci 26:10626-10630.
Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF (2005) A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 25:3379-3388.
Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68.
Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R (2006) LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer 118:2703-2710.
Bartkowska K, Turlejski K, Djavadian RL (2010) Neurotrophins and their receptors in early development of the mammalian nervous system. Acta Neurobiol Exp (Wars) 70:454-467.
Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell B 39:1071-1076.
Bernard O, Ganiatsas S, Kannourakis G, Dringen R (1994) Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ 5:1159-1171.
Birkenfeld J, Betz H, Roth D (2001) Inhibition of neurite extension by overexpression of individual domains of LIM kinase 1. J Neurochem 78:924-927.
Buchan AM, Lin CY, Choi J, Barber DL (2002) Somatostatin, acting at receptor subtype 1, inhibits Rho activity, the assembly of actin stress fibers, and cell migration. J Biol Chem 277:28431-28438.
Chao MV (2003) Neurotrophins and their receptors:a convergence point for many signalling pathways. Nat Rev Neurosci 4:299-309.
Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM (2011) Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci U S A 108:18430-18435.
Claus C, Chey S, Heinrich S, Reins M, Richardt B, Pinkert S, Fechner H, Gaunitz F, Schafer I, Seibel P, Liebert UG (2011) Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus. Journal of Virology 85:3881-3892.
Cosker KE, Shadan S, van Diepen M, Morgan C, Li M, Allen-Baume V, Hobbs C, Doherty P, Cockcroft S, Eickholt BJ (2008) Regulation of PI3K signalling by the phosphatidylinositol transfer protein PITPalpha during axonal extension in hippocampal neurons. J Cell Sci 121:796-803.
Cunha C, Brambilla R, Thomas KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3:1.
Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754-9763.
Endo M, Ohashi K, Mizuno K (2007) LIM kinase and slingshot are critical for neurite extension. J Biol Chem 282:13692-13702.
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527-2537.
Gehler S, Gallo G, Veien E, Letourneau PC (2004) p75 neurotrophin receptor signaling regulates growth cone filopodial dynamics through modulating RhoA activity. J Neurosci 24:4363-4372.
Goldberg JL (2003) How does an axon grow? Genes Dev 17:941-958.
Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA (2002) Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 33:689-702.
Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1-49.
Heitz F, Morris MC, Divita G (2009) Twenty years of cell-penetrating peptides:from molecular mechanisms to therapeutics. Br J Pharmacol 157:195-206.
Horita Y, Ohashi K, Mukai M, Inoue M, Mizuno K (2008) Suppression of the invasive capacity of rat ascites hepatoma cells by knockdown of Slingshot or LIM kinase. J Biol Chem 283:6013-6021.
Labelle C, Leclerc N (2000) Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons. Brain Res Dev Brain Res 123:1-11.
Li R, Soosairajah J, Harari D, Citri A, Price J, Ng HL, Morton CJ, Parker MW, Yarden Y, Bernard O (2006) Hsp90 increases LIM kinase activity by promoting its homo-dimerization. Faseb J 20:1218-1220.
Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86-98.
Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774-3786.
Matsui S, Matsumoto S, Adachi R, Kusui K, Hirayama A, Watanabe H, Ohashi K, Mizuno K, Yamaguchi T, Kasahara T, Suzuki K (2002) LIM kinase 1 modulates opsonized zymosan-triggered activation of macrophage-like U937 cells. Possible involvement of phosphorylation of cofilin and reorganization of actin cytoskeleton. J Biol Chem 277:544-549.
Meng YH, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jial ZP (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121-133.
Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401-414.
Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiaml, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-10449.
Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T (2010) Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc Natl Acad Sci U S A 107:7586-7591.
Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K (2006) A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol 126:627-638.
Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7:276-285.
Proschel C, Blouin MJ, Gutowski NJ, Ludwig R, Noble M (1995) Limkl is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro. Oncogene 11:1271-1281.
Purcell AL, Carew TJ (2003) Tyrosine kinases, synaptic plasticity and memory:insights from vertebrates and invertebrates. Trends Neurosci 26:625-630.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-3029.
Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T, Quiroga S, Ferreira A, Caceres A (2004) LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell 15:3433-3449.
Santos AR, Comprido D, Duarte CB (2010) Regulation of local translation at the synapse by BDNF. Prog Neurobiol 92:505-516.
Schecterson LC, Bothwell M (2010) Neurotrophin Receptors:Old Friends with New Partners. Developmental Neurobiology 70:332-338.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283-289.
Scott RW, Olson MF (2007) LIM kinases:function, regulation and association with human disease. J Mol Med (Berl) 85:555-568.
Shen K, Cowan CW (2010) Guidance molecules in synapse formation and plasticity. Cold Spring Harb Perspect Biol 2:a001842.
Tahirovic S, Bradke F (2009) Neuronal polarity. Cold Spring Harb Perspect Biol 1:a001644.
Takahashi H, Koshimizu U, Nakamura T (1998) A novel transcript encoding truncated LIM kinase 2 is specifically expressed in male germ cells undergoing meiosis. Biochem Biophys Res Commun 249:138-145.
Toda S, Shen HW, Peters J, Cagle S, Kalivas PW (2006) Cocaine increases actin cycling:effects in the reinstatement model of drug seeking. Journal of Neuroscience 26:1579-1587.
Tucker KL (2002) Neurotrophins and the control of axonal outgrowth. Panminerva Med 44:325-333.
Tursun B, Schluter A, Peters MA, Viehweger B, Ostendorff HP, Soosairajah J, Drung A, Bossenz M, Johnsen SA, Schweizer M, Bernard O, Bach I (2005) The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 19:2307-2319.
Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation:on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224-237.
Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137-149.
Zhao L, Sheng AL, Huang SH, Yin YX, Chen B, Li XZ, Zhang Y, Chen ZY (2009) Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface. J Cell Sci 122:3123-3136.
Agnew BJ, Minamide LS, Bamburg JR (1995) Reactivation of phosphorylated actin depolymerizing factor and identification of the regulatory site. J Biol Chem 270:17582-17587.
Aizawa H, Wakatsuki S, Ishii A, Moriyama K, Sasaki Y, Ohashi K, Sekine-Aizawa Y, Sehara-Fujisawa A, Mizuno K, Goshima Y, Yahara I (2001) Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nat Neurosci 4:367-373.
Allen PG (2003) Actin filament uncapping localizes to ruffling lamellae and rocketing vesicles. Nat Cell Biol 5:972-979.
Anggono V, Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 22:461-469.
Aunis D, Bader MF (1988) The cytoskeleton as a barrier to exocytosis in secretory cells. J Exp Biol 139:253-266.
Baas PW, Buster DW (2004) Slow axonal transport and the genesis of neuronal morphology. J Neurobiol 58:3-17.
Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R (2006) LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer 118:2703-2710.
Bakin AV, Safina A, Rinehart C, Daroqui C, Darbary H, Helfman DM (2004) A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 15:4682-4694.
Bamburg JR (1999) Proteins of the ADF/cofilin family:essential regulators of actin dynamics. Annu Rev Cell Dev Biol 15:185-230.
Barkalow KL, Italiano JE, Jr., Chou DE, Matsuoka Y, Bennett V, Hartwig JH (2003) Alpha-adducin dissociates from F-actin and spectrin during platelet activation. J Cell Biol 161:557-570.
Barrett D, Shumake J, Jones D, Gonzalez-Lima F (2003) Metabolic mapping of mouse brain activity after extinction of a conditioned emotional response. J Neurosci 23:5740-5749.
Bartkowska K, Turlejski K, Djavadian RL (2010) Neurotrophins and their receptors in early development of the mammalian nervous system. Acta Neurobiol Exp (Wars) 70:454-467.
Barzik M, Kotova TI, Higgs HN, Hazelwood L, Hanein D, Gertler FB, Schafer DA (2005) Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins. J Biol Chem 280:28653-28662.
Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell B 39:1071-1076.
Bernard O, Ganiatsas S, Kannourakis G, Dringen R (1994) Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ 5:1159-1171.
Bernstein BW, Bamburg JR (2010a) ADF/Cofilin:a functional node in cell biology. Trends Cell Biol 20:187-195.
Bernstein BW, Bamburg JR (2010b) ADF/cofilin:a functional node in cell biology. Trends Cell Biol 20:187-195.
Bi AL, Wang Y, Li BQ, Wang QQ, Ma L, Yu H, Zhao L, Chen ZY (2010) Region-specific involvement of actin rearrangement-related synaptic structure alterations in conditioned taste aversion memory. Learn Mem 17:420-427.
Birkenfeld J, Betz H, Roth D (2001) Inhibition of neurite extension by overexpression of individual domains of LIM kinase 1. J Neurochem 78:924-927.
Bradke F, Dotti CG (1999) The role of local actin instability in axon formation. Science 283:1931-1934.
Bradke F, Dotti CG (2000) Establishment of neuronal polarity:lessons from cultured hippocampal neurons. Curr Opin Neurobiol 10:574-581.
Bramham CR (2008) Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol 18:524-531.
Broderick MJ, Winder SJ (2005) Spectrin, alpha-actinin, and dystrophin. Adv Protein Chem 70:203-246.
Bubb MR, Yarmola EG, Gibson BG, Southwick FS (2003) Depolymerization of actin filaments by profilin. Effects of profilin on capping protein function. J Biol Chem 278:24629-24635.
Buchan AM, Lin CY, Choi J, Barber DL (2002) Somatostatin, acting at receptor subtype 1, inhibits Rho activity, the assembly of actin stress fibers, and cell migration. J Biol Chem 277:28431-28438.
Carlisle HJ, Kennedy MB (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182-187.
Carlisle HJ, Manzerra P, Marcora E, Kennedy MB (2008) SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J Neurosci 28:13673-13683.
Chao MV (2003) Neurotrophins and their receptors:a convergence point for many signalling pathways. Nat Rev Neurosci 4:299-309.
Chen LY, Rex CS, Casale MS, Gall CM, Lynch G (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci 27:5363-5372.
Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM (2011) Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci U S A 108:18430-18435.
Cingolani LA, Goda Y (2008) Actin in action:the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9:344-356.
Claus C, Chey S, Heinrich S, Reins M, Richardt B, Pinkert S, Fechner H, Gaunitz F, Schafer I, Seibel P, Liebert UG (2011) Involvement of p32 and Microtubules in Alteration of Mitochondrial Functions by Rubella Virus. Journal of Virology 85:3881-3892.
Cosker KE, Shadan S, van Diepen M, Morgan C, Li M, Allen-Baume V, Hobbs C, Doherty P, Cockcroft S, Eickholt BJ (2008) Regulation of PI3K signalling by the phosphatidylinositol transfer protein PITPalpha during axonal extension in hippocampal neurons. J Cell Sci 121:796-803.
Cunha C, Brambilla R, Thomas KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3:1.
Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754-9763.
Davis M, Ressler K, Rothbaum BO, Richardson R (2006) Effects of D-cycloserine on extinction:translation from preclinical to clinical work. Biol Psychiatry 60:369-375.
DesMarais V, Ghosh M, Eddy R, Condeelis J (2005) Cofilin takes the lead. J Cell Sci 118:19-26.
Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, Di Fiore PP, Scita G (2004) Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol 6:1180-1188.
Dormann D, Weijer CJ (2006) Chemotactic cell movement during Dictyostelium development and gastrulation. Curr Opin Genet Dev 16:367-373.
Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI (2005) Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123:903-915.
During RL, Li W, Hao B, Koenig JM, Stephens DS, Quinn CP, Southwick FS (2005) Anthrax lethal toxin paralyzes neutrophil actin-based motility. J Infect Dis 192:837-845.
Eitzen G (2003) Actin remodeling to facilitate membrane fusion. Biochim Biophys Acta 1641:175-181.
Endo M, Ohashi K, Mizuno K (2007) LIM kinase and slingshot are critical for neurite extension. J Biol Chem 282:13692-13702.
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003a) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527-2537.
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003b) Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527-2537.
Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P (2005) The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem J 389:127-135.
Fass J, Gehler S, Sarmiere P, Letourneau P, Bamburg JR (2004) Regulating filopodial dynamics through actin-depolymerizing factor/cofilin. Anat Sci Int 79:173-183.
Feng Y, Walsh CA (2004) The many faces of filamin:a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6:1034-1038.
Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825-838.
Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2004) Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear. J Neurosci 24:1962-1966.
Fischer RS, Fowler VM (2003) Tropomodulins:life at the slow end. Trends Cell Biol 13:593-601.
Forscher P, Smith SJ (1988) Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J Cell Biol 107:1505-1516.
Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexinl-dependent mechanism. Nat Neurosci 10:67-76.
Fukata Y, Kimura T, Kaibuchi K (2002) Axon specification in hippocampal neurons. Neurosci Res 43:305-315.
Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38:447-460.
Gardel ML, Nakamura F, Hartwig JH, Crocker JC, Stossel TP, Weitz DA (2006) Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc Natl Acad Sci U S A 103:1762-1767.
Gardel ML, Shin JH, MacKintosh FC, Mahadevan L, Matsudaira P, Weitz DA (2004) Elastic behavior of cross-linked and bundled actin networks. Science 304:1301-1305.
Gehler S, Gallo G, Veien E, Letourneau PC (2004) p75 neurotrophin receptor signaling regulates growth cone filopodial dynamics through modulating RhoA activity. J Neurosci 24:4363-4372.
Goldberg JL (2003) How does an axon grow? Genes Dev 17:941-958.
Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA (2002) Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 33:689-702.
Gouin E, Welch MD, Cossart P (2005) Actin-based motility of intracellular pathogens. Curr Opin Microbiol 8:35-45.
Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1-49.
Grummt I (2006) Actin and myosin as transcription factors. Curr Opin Genet Dev 16:191-196.
Gu JP, Lee CW, Fan YJ, Komlos D, Tang X, Sun CC, Yu KA, Hartzell HC, Chen G, Bamburg JR, Zheng JQ (2010) ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13:1208-1215.
. Heitz F, Morris MC, Divita G (2009) Twenty years of cell-penetrating peptides:from molecular mechanisms to therapeutics. Br J Pharmacol 157:195-206.
Hering H, Sheng M (2003) Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J Neurosci 23:11759-11769.
Higgs HN (2005) Formin proteins:a domain-based approach. Trends Biochem Sci 30:342-353.
Hollingsworth EB, McNeal ET, Burton JL, Williams RJ, Daly JW, Creveling CR (1985) Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3':5'-monophosphate-generating systems, receptors, and enzymes. J Neurosci 5:2240-2253.
Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H (2008) The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57:719-729.
Horita Y, Ohashi K, Mukai M, Inoue M, Mizuno K (2008) Suppression of the invasive capacity of rat ascites hepatoma cells by knockdown of Slingshot or LIM kinase. J Biol Chem 283:6013-6021.
Hotulainen P, Hoogenraad CC (2010) Actin in dendritic spines: connecting dynamics to function. J Cell Biol 189:619-629.
Hou YY, Lu B, Li M, Liu Y, Chen J, Chi ZQ, Liu JG (2009) Involvement of actin rearrangements within the amygdala and the dorsal hippocampus in aversive memories of drug withdrawal in acute morphine-dependent rats. J Neurosci 29:12244-12254.
Iki J, Inoue A, Bito H, Okabe S (2005) Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity. Eur J Neurosci 22:2985-2994.
Joels G, Lamprecht R (2010) Interaction between N-ethylmaleimide-sensitive factor and GluR2 is essential for fear memory formation in lateral amygdala. J Neurosci 30:15981-15986.
Kullmann DM (2003) Silent synapses:what are they telling us about long-term potentiation? Philos Trans R Soc Lond B Biol Sci 358:727-733.
Kumar N, Tomar A, Parrill AL, Khurana S (2004) Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J Biol Chem 279:45036-45046.
Labelle C, Leclerc N (2000) Exogenous BDNF, NT-3 and NT-4 differentially regulate neurite outgrowth in cultured hippocampal neurons. Brain Res Dev Brain Res 123:1-11.
Landsverk ML, Epstein HF (2005) Genetic analysis of myosin Ⅱ assembly and organization in model organisms. Cell Mol Life Sci 62:2270-2282.
Li R, Soosairajah J, Harari D, Citri A, Price J, Ng HL, Morton CJ, Parker MW, Yarden Y, Bernard O (2006) Hsp90 increases LIM kinase activity by promoting its homo-dimerization. Faseb J 20:1218-1220.
Linder S, Kopp P (2005) Podosomes at a glance. J Cell Sci 118:2079-2082.
Littlefield R, Almenar-Queralt A, Fowler VM (2001) Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nat Cell Biol 3:544-551.
Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86-98.
Lua BL, Low BC (2005) Cortactin phosphorylation as a switch for actin cytoskeletal network and cell dynamics control. FEBS Lett 579:577-585.
Luikart BW, Nef S, Virmani T, Lush ME, Liu Y, Kavalali ET, Parada LF (2005) TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses. J Neurosci 25:3774-3786.
Mantzur L, Joels G, Lamprecht R (2009) Actin polymerization in lateral amygdala is essential for fear memory formation. Neurobiol Learn Mem 91:85-88.
Matsui S, Matsumoto S, Adachi R, Kusui K, Hirayama A, Watanabe H, Ohashi K, Mizuno K, Yamaguchi T, Kasahara T, Suzuki K (2002) LIM kinase 1 modulates opsonized zymosan-triggered activation of macrophage-like U937 cells. Possible involvement of phosphorylation of cofilin and reorganization of actin cytoskeleton. J Biol Chem 277:544-549.
Matus A (2000) Actin-based plasticity in dendritic spines. Science 290:754-758.
Meng YH, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jial ZP (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121-133.
Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70-74.
Miller G (2004) Forgetting and remembering. Learning to forget. Science 304:34-36.
Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401-414.
Mirzapoiazova T, Kolosova IA, Romer L, Garcia JG, Verin AD (2005) The role of caldesmon in the regulation of endothelial cytoskeleton and migration. J Cell Physiol 203:520-528.
Mitchison TJ, Cramer LP (1996) Actin-based cell motility and cell locomotion. Cell 84:371-379.
Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444-10449.
Mizui T, Takahashi H, Sekino Y, Shirao T (2005) Overexpression of drebrin A in immature neurons induces the accumulation of F-actin and PSD-95 into dendritic filopodia, and the formation of large abnormal protrusions. Mol Cell Neurosci 30:630-638.
Motanis H, Maroun M (2012) Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning. Hippocampus 22:494-500.
Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36:567-584.
Nakamura F, Osborn E, Janmey PA, Stossel TP (2002) Comparison of filamin A-induced cross-linking and Arp2/3 complex-mediated branching on the mechanics of actin filaments. J Biol Chem 277:9148-9154.
Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T (2010) Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc Natl Acad Sci U S A 107:7586-7591.
Nicholson-Dykstra S, Higgs HN, Harris ES (2005) Actin dynamics: growth from dendritic branches. Curr Biol 15:R346-357.
Niggli V (2005) Regulation of protein activities by phosphoinositide phosphates. Annu Rev Cell Dev Biol 21:57-79.
Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K (2006) A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol 126:627-638.
Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7:276-285.
Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates. New York:Academic.
Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE, Huganir RL (2003) Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37:263-274.
Proschel C, Blouin MJ, Gutowski NJ, Ludwig R, Noble M (1995) Limkl is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro. Oncogene 11:1271-1281.
Purcell AL, Carew TJ (2003) Tyrosine kinases, synaptic plasticity and memory:insights from vertebrates and invertebrates. Trends Neurosci 26:625-630.
Rafelski SM, Theriot JA (2004) Crawling toward a unified model of cell mobility:spatial and temporal regulation of actin dynamics. Annu Rev Biochem 73:209-239.
Rehberg K, Bergado-Acosta JR, Koch JC, Stork O (2010) Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala. Neurobiol Learn Mem 94:117-126.
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-3029.
Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T, Quiroga S, Ferreira A, Caceres A (2004) LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell 15:3433-3449.
Rust MB, Gurniak CB, Renner M, Vara H, Morando L, Gorlich A, Sassoe-Pognetto M, Al Banchaabouchi M, Giustetto M, Triller A, Choquet D, Witke W (2010) Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. Embo J 29:1889-1902.
Sananbenesi F, Fischer A, Wang XY, Schrick C, Neve R, Radulovic J, Tsai LH (2007) A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci 10:1012-1019.
Santos AR, Comprido D, Duarte CB (2010) Regulation of local translation at the synapse by BDNF. Prog Neurobiol 92:505-516.
Schecterson LC, Bothwell M (2010) Neurotrophin Receptors:Old Friends with New Partners. Developmental Neurobiology 70:332-338.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283-289.
Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7:923-929.
Scott RW, Olson MF (2007) LIM kinases:function, regulation and association with human disease. J Mol Med (Berl) 85:555-568.
Shen K, Cowan CW (2010) Guidance molecules in synapse formation and plasticity. Cold Spring Harb Perspect Biol 2:a001842.
Stradal TE, Scita G (2006) Protein complexes regulating Arp2/3-mediated actin assembly. Curr Opin Cell Biol 18:4-10.
Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95-101.
Tahirovic S, Bradke F (2009) Neuronal polarity. Cold Spring Harb Perspect Biol 1:a001644.
Takahashi H, Koshimizu U, Nakamura T (1998) A novel transcript encoding truncated LIM kinase 2 is specifically expressed in male germ cells undergoing meiosis. Biochem Biophys Res Commun 249:138-145.
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683-1687.
Toda S, Shen HW, Peters J, Cagle S, Kalivas PW (2006) Cocaine increases actin cycling:effects in the reinstatement model of drug seeking. Journal of Neuroscience 26:1579-1587.
Tucker KL (2002) Neurotrophins and the control of axonal outgrowth. Panminerva Med 44:325-333.
Tursun B, Schluter A, Peters MA, Viehweger B, Ostendorff HP, Soosairajah J, Drung A, Bossenz M, Johnsen SA, Schweizer M, Bernard O, Bach I (2005) The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 19:2307-2319.
Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation:on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224-237.
Tyler WJ, Pozzo-Miller LD (2001) BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 21:4249-4258.
Van Troys M, Huyck L, Leyman S, Dhaese S, Vandekerkhove J, Ampe C (2008) Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol 87:649-667.
Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118:4917-4919.
Villasana LE, Klann E, Tejada-Simon MV (2006) Rapid isolation of synaptoneurosomes and postsynaptic densities from adult mouse hippocampus. J Neurosci Methods 158:30-36.
Yang C, Pring M, Wear MA, Huang M, Cooper JA, Svitkina TM, Zigmond SH (2005) Mammalian CARMIL inhibits actin filament capping by capping protein. Dev Cell 9:209-221.
Yao Y, Kelly MT, Sajikumar S, Serrano P, Tian D, Bergold PJ, Frey JU, Sacktor TC (2008) PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J Neurosci 28:7820-7827.
Yarmola EG, Bubb MR (2004) Effects of profilin and thymosin beta4 on the critical concentration of actin demonstrated in vitro and in cell extracts with a novel direct assay. J Biol Chem 279:33519-33527.
Yin HL, Janmey PA (2003) Phosphoinositide regulation of the actin cytoskeleton. Annu Rev Physiol 65:761-789.
Yoshimura T, Arimura N, Kaibuchi K (2006) Signaling networks in neuronal polarization. J Neurosci 26:10626-10630.
Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137-149.
Yuen EY, Liu W, Kafri T, van Praag H, Yan Z (2010) Regulation of AMPA receptor channels and synaptic plasticity by cofilin phosphatase Slingshot in cortical neurons. J Physiol 588:2361-2371.
Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF (2005) A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 25:3379-3388.
Zhao L, Sheng AL, Huang SH, Yin YX, Chen B, Li XZ, Zhang Y, Chen ZY (2009) Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface. J Cell Sci 122:3123-3136.
Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55:53-68.
Zhou Q, Xiao M, Nicoll RA (2001) Contribution of cytoskeleton to the internalization of AMPA receptors. Proc Natl Acad Sci U S A 98:1261-1266.
Zhou Z, Hu J, Passafaro M, Xie W, Jia Z (2011) GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. J Neurosci 31:819-833.
Zushida K, Sakurai M, Wada K, Sekiguchi M (2007) Facilitation of extinction learning for contextual fear memory by PEPA:a potentiator of AMPA receptors. J Neurosci 27:158-166.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |