DJ-1基因表达分析与功能研究及构建在多巴胺能神经元过表达tTA的基因敲入小鼠
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摘要
帕金森病(Parkinson's disease, PD)是仅次于阿尔茨海默病的第二大神经退行性疾病。在60岁以上人群中,其发病率约为1%,在80岁以上人群中这一数据上升至4%。帕金森病临床上的主要特征是运动功能损伤,例如运动迟缓、震颤、肌肉僵直、步态异常和姿势不稳。帕金森病在病理学上的主要特征是路易小体形成和黑质多巴胺能神经元选择性丢失。最近取得的研究进展极大的增强了对帕金森病的理解和认识,这将为帕金森病的治疗提供理论依据。而人类遗传学方面的研究进展则使得我们能够鉴定与家族性帕金森病相关的致病基因,DJ-1就是通过遗传学连锁分析发现的第三个家族性PD致病基因,这些重要的发现为我们研究帕金森病的致病机理及治疗帕金森病奠定了坚实的基础。
DJ-1属于ThiJ/PfpI蛋白超家族,DJ-1蛋白在各个物种中比较保守,小鼠DJ-1与人DJ-1的同源性高达90%。DJ-1基因位于人染色体1p36,全长24kb,共有7个外显子,其中外显子1A和1B不参与编码蛋白质,并且具有两种剪接方式,2-7号外显子包含开放阅读框,其编码区全长567bp,编码含有189个氨基酸残基、分子量约20kD的DJ-1蛋白。DJ-1基因突变如何导致帕金森病的发生到目前为止仍不清楚。但越来越多的证据表明DJ-1基因可能在氧化应激、线粒体损伤、泛素蛋白酶体系统以及mRNA转录后修饰的调控中发挥作用。DJ-1是作为原癌基因被发现的,而且被证明具有氧化应激感应器的功能。Northern杂交分析表明,DJ-1mRNA广泛表达,存在于人体各个组织中,包括脑、心、肝、胰腺、肾、骨骼肌、胎盘中,提示DJ-1具有广泛的功能。已有研究小组对DJ-1基因在人脑及啮齿类动物脑中的表达模式做了分析,但是他们的研究结果存在很大的争议,其中主要的争议在于DJ-1基因是表达于神经元中,还是表达于神经胶质细胞中,并且DJ-1基因是否表达于多巴胺能神经元中。在人脑中,争议的焦点在于DJ-1基因是表达在神经元中还是神经胶质细胞中。在啮齿类动物脑中,DJ-1是否表达于黑质的多巴胺能神经元中仍存在争议。
利用DJ-1基因敲除小鼠作为阴性对照,我们研究了DJ-1在成年小鼠大脑中的表达模式和功能。通过原位杂交和免疫组化技术相结合,我们在经过DJ-1原位杂交的玻片上进行了TH、NeuN和GFAP的免疫组化实验,我们发现DJ-1 mRNA在超过96%的神经元里表达,而在神经胶质细胞中没有DJ-1mRNA的表达。黑质的所有多巴胺能神经元均表达DJ-1mRNA。值得一提的是,脉络丛和室管膜上皮细胞高表达DJ-1 mRNA。DJ-1广泛的表达模式提示我们DJ-1具有一些基本的功能。随后通过免疫组化实验,我们发现DJ-1蛋白也不存在于神经胶质细胞内,而令人惊奇的是,DJ-1蛋白质不存在于神经元内,而且DJ-1的染色是弥漫性的。我们根据已有的证据推测DJ-1是通过神经元轴突运输并分泌到细胞外的,通过轴突运输抑制剂colchicine处理,DJ-1积累在神经元内。小鼠脑脊液中检测到了DJ-1的存在。另外大量的DJ-1在小鼠大脑皮层原代神经元的培养基中检测到,这些实验结果证实了我们的假设。
多巴胺能神经元变性死亡和功能异常被认为是帕金森病发病的主要原因,多巴胺能神经元的保护因子和风险因子的研究已经取得了很大的进展,但是到目前为止,我们很难在动物体内阐明这些因子的作用。在这一方面,我们已经取得了一些研究进展,就是在多巴胺能神经元中特异的敲除感兴趣的基因。在过去的几年时间里,我们致力于研究在一种可调控的模式下,在多巴胺能神经元中过表达任意一个感兴趣的基因。基于这些前期研究,我们计划利用一种新的策略来实现这个目标,这个实验的基本思想是将一个正反馈作用元件基因打靶到多巴胺能神经元特异性的启动子之后,从而实现选择性的在多巴胺能神经元中过表达感兴趣的基因,这个正反馈作用元件将作为扩增子来促进目的基因的大量表达。正反馈作用原件将利用双向的tetO启动子,并作为扩增子加速转基因的表达,多巴胺转运蛋白(dopamine transporter, DAT)启动子将控制基因表达的特异性,我们希望此设计可以实现在多巴胺能神经元中特异性、可调控性的表达感兴趣的基因。
我们构建了ES细胞基因打靶载体,顺利的进行了ES细胞同源打靶,通过Southern杂交鉴定出了阳性的ES细胞克隆。并且我们对这些阳性的克隆,用5’和3’端的探针重新进行了Southern杂交鉴定。随后我们准备了ES细胞进行显微注射,已经得到含有tTA和CHR2-mCherry基因的嵌合体小鼠,与C57BL/6杂交后,具有灰色皮肤的杂合子小鼠已经长大。这些杂合子小鼠将被用来进行tTA和转基因的表达特异性和表达丰度鉴定,并且我们还将利用doxycycline来调控这些转基因的表达。
总之,我们发现DJ-1mRNA在超过96%的神经元里表达,但不在神经胶质细胞里表达,而且DJ-1在黑质的所有多巴胺能神经元里都有表达。DJ-1是通过神经元轴突运输并被分泌到细胞外,这提示我们DJ-1在细胞外具有重要的保护神经元功能。这一发现对于最终阐明DJ-1缺失导致帕金森病的发病机理具有重要意义。我们还构建了一个在多巴胺能神经元中特异性过表达tTA基因的基因敲入小鼠,该小鼠的转基因表达,以及是否受doxycycline的调控将会在以后的工作中继续研究。这一动物模型的建立为研究基因特别是帕金森病相关基因在多巴胺能神经元中的分子通路以及多巴胺能神经元退化提供了一个重要的实验手段。
Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders in the world. It affects about 1% of the population above the age of 60. Clinically, PD is characterized by slowness of movement, rest tremor, rigidity, and disturbances in balance. Pathologically, PD is characterized by the presence of Lewy bodies and selective loss of dopaminergic neuron in the substantia nigra pars compacta (SNc). The dopaminergic neuronal cell death leads to the loss of dopamine (DA) in the striatum and in the SNc. Recent research has enhanced our understanding in PD and this will certainly improve the approaches that can be used in the treatment of PD. Advances in human genetics have enabled us to identify genes that are linked to rare forms of familial PD. DJ-1 is the third gene discovered that to be linked to familial Parkinson's disease by linkage analysis in 2003. These important findings serve as the foundation for discovering new pathways that may lead to the development of new therapies for PD.
DJ-1 belongs to the ThiJ/PfpI superfamily and is well conserved among species. Human DJ-1 coding region consists of 567 nucleotides and encodes a 20kd protein. Mouse DJ-1 shares 90% amino acid homology with human DJ-1. DJ-1 deficient mice are fertile and viable, They display mild movement impairment, dopaminergic dysfunction without dopamine neuron degeneration. The molecular mechanism for DJ-1 mutation related familial Parkinson's disease is still unknown. Several studies suggested DJ-1 may be involved in mitochondria, oxidative sensoring, ubiquitin proteasome system and post-transcriptional regulation control. Moreover, DJ-1, initially discovered as an oncogene and oxidative stress sensor, is increased in serum and cerebrospinal fluid (CSF) of several types of cancers and neurological disorders and might be a novel biomarker for these disease conditions. Northern blot showed DJ-1 mRNA present in all tissues examined, suggesting ubiquitous function of DJ-1. Several studies have examined the expression pattern of DJ-1 in brains of both human and rodents. Surprisingly, these studies generated considerably conflicting results. The major controversy is whether DJ-1 is expressed in neurons or astrocytes and whether DJ-1 is expressed in dopamine neuron. In human brain, it is rather controversial whether DJ-1 is expressed in astrocytes or in neurons. In rodent brains, it is not clear whether DJ-1 is expressed in dopamine neuron in substantia nigra.
Using DJ-1 deficient mouse as negative control, we examined DJ-1 mRNA expression in mouse brains. By sequential double labeling on the same sections, in situ hybridization of DJ-1 mRNA was followed by immunofluorescence detection for TH, NeuN and GFAP. We found DJ-1 mRNA was expressed by greater than 96% neurons but undetectable in astrocytes in most brain regions. All dopamine neurons in ventral midbrain expressed DJ-1 mRNA. Interestingly, choroid plexus and ependymal cells lining ventricles strongly expressed DJ-1 mRNA. The ubiquitous neuronal expression of DJ-1 suggests its fundamental roles underlying neuronal functions. By immunohistochemistry, we found DJ-1 protein is not co-localized with astrocytes. To our surprise, DJ-1 protein is not colocalized with neurons, and the DJ-1 staining is diffused in mouse brain, we then proposed that DJ-1 is axonal transported and secreted by neurons. By colchicine treatment, CSF, and primary neuron culture experiments, we confirmed our hypothesis.
Molecular and genetic studies have made significant progress in revealing protective or risk factors for dopamine neuron survival and dysfunction in Parkinson's disease. However, there is no good genetic approach for high level gene expression in dopamine neuron to test their biological significance in living animals. To overexpress transgene in dopamine neurons, we propose to gene target (knockin) "positive-feedback cassette" into endogenous locus of dopamine transporter (DAT). Positive-feedback cassette will serve as an amplifier to boost transgene expression using bi-directional tetO promoter and DAT locus will favor transgene expression in dopamine neuron. We expect this unique "in situ amplifier" design will achieve doxycycline regulated transgene overexpression specifically in dopamine neurons. The proposed project aims to lay the groundwork for making regulatable tissue specific transgenic overexpression models for future projects in our lab as well as for the entire scientific community.
We constructed ES cell targeting vector, successfully performed ES cell targeting and identified positive targeted ES clones with high targeting efficiency. The identified positive clones were re-amplified and confirmed by southern blot with both 5'and 3'probes. Microinjection is done after we prepared the positive ES cell clones. Chimera mice was got, and we then crossed with C57BL/6 mice, the heterozygous mice with agouti fur will be used to characterize tTA expression pattern and characterize the time course of transgene expression induction by dietary doxycycline in the future.
In summary, we found DJ-1mRNA was expressed by greater than 96% neurons but undetectable in astrocytes in most brain regions. All dopamine neurons in ventral midbrain expressed DJ-1 mRNA. DJ-1 is axonal transported and secreted by neurons.And we generated a knockin mice, the expression pattern of tTA and ChR2-mCherry selectively in dopamine neurons via regulated expression will be done in the future.
DJ-1属于ThiJ/PfpI蛋白超家族,DJ-1蛋白在各个物种中比较保守,小鼠DJ-1与人DJ-1的同源性高达90%。DJ-1基因位于人染色体1p36,全长24kb,共有7个外显子,其中外显子1A和1B不参与编码蛋白质,并且具有两种剪接方式,2-7号外显子包含开放阅读框,其编码区全长567bp,编码含有189个氨基酸残基、分子量约20kD的DJ-1蛋白。DJ-1基因突变如何导致帕金森病的发生到目前为止仍不清楚。但越来越多的证据表明DJ-1基因可能在氧化应激、线粒体损伤、泛素蛋白酶体系统以及mRNA转录后修饰的调控中发挥作用。DJ-1是作为原癌基因被发现的,而且被证明具有氧化应激感应器的功能。Northern杂交分析表明,DJ-1mRNA广泛表达,存在于人体各个组织中,包括脑、心、肝、胰腺、肾、骨骼肌、胎盘中,提示DJ-1具有广泛的功能。已有研究小组对DJ-1基因在人脑及啮齿类动物脑中的表达模式做了分析,但是他们的研究结果存在很大的争议,其中主要的争议在于DJ-1基因是表达于神经元中,还是表达于神经胶质细胞中,并且DJ-1基因是否表达于多巴胺能神经元中。在人脑中,争议的焦点在于DJ-1基因是表达在神经元中还是神经胶质细胞中。在啮齿类动物脑中,DJ-1是否表达于黑质的多巴胺能神经元中仍存在争议。
利用DJ-1基因敲除小鼠作为阴性对照,我们研究了DJ-1在成年小鼠大脑中的表达模式和功能。通过原位杂交和免疫组化技术相结合,我们在经过DJ-1原位杂交的玻片上进行了TH、NeuN和GFAP的免疫组化实验,我们发现DJ-1 mRNA在超过96%的神经元里表达,而在神经胶质细胞中没有DJ-1mRNA的表达。黑质的所有多巴胺能神经元均表达DJ-1mRNA。值得一提的是,脉络丛和室管膜上皮细胞高表达DJ-1 mRNA。DJ-1广泛的表达模式提示我们DJ-1具有一些基本的功能。随后通过免疫组化实验,我们发现DJ-1蛋白也不存在于神经胶质细胞内,而令人惊奇的是,DJ-1蛋白质不存在于神经元内,而且DJ-1的染色是弥漫性的。我们根据已有的证据推测DJ-1是通过神经元轴突运输并分泌到细胞外的,通过轴突运输抑制剂colchicine处理,DJ-1积累在神经元内。小鼠脑脊液中检测到了DJ-1的存在。另外大量的DJ-1在小鼠大脑皮层原代神经元的培养基中检测到,这些实验结果证实了我们的假设。
多巴胺能神经元变性死亡和功能异常被认为是帕金森病发病的主要原因,多巴胺能神经元的保护因子和风险因子的研究已经取得了很大的进展,但是到目前为止,我们很难在动物体内阐明这些因子的作用。在这一方面,我们已经取得了一些研究进展,就是在多巴胺能神经元中特异的敲除感兴趣的基因。在过去的几年时间里,我们致力于研究在一种可调控的模式下,在多巴胺能神经元中过表达任意一个感兴趣的基因。基于这些前期研究,我们计划利用一种新的策略来实现这个目标,这个实验的基本思想是将一个正反馈作用元件基因打靶到多巴胺能神经元特异性的启动子之后,从而实现选择性的在多巴胺能神经元中过表达感兴趣的基因,这个正反馈作用元件将作为扩增子来促进目的基因的大量表达。正反馈作用原件将利用双向的tetO启动子,并作为扩增子加速转基因的表达,多巴胺转运蛋白(dopamine transporter, DAT)启动子将控制基因表达的特异性,我们希望此设计可以实现在多巴胺能神经元中特异性、可调控性的表达感兴趣的基因。
我们构建了ES细胞基因打靶载体,顺利的进行了ES细胞同源打靶,通过Southern杂交鉴定出了阳性的ES细胞克隆。并且我们对这些阳性的克隆,用5’和3’端的探针重新进行了Southern杂交鉴定。随后我们准备了ES细胞进行显微注射,已经得到含有tTA和CHR2-mCherry基因的嵌合体小鼠,与C57BL/6杂交后,具有灰色皮肤的杂合子小鼠已经长大。这些杂合子小鼠将被用来进行tTA和转基因的表达特异性和表达丰度鉴定,并且我们还将利用doxycycline来调控这些转基因的表达。
总之,我们发现DJ-1mRNA在超过96%的神经元里表达,但不在神经胶质细胞里表达,而且DJ-1在黑质的所有多巴胺能神经元里都有表达。DJ-1是通过神经元轴突运输并被分泌到细胞外,这提示我们DJ-1在细胞外具有重要的保护神经元功能。这一发现对于最终阐明DJ-1缺失导致帕金森病的发病机理具有重要意义。我们还构建了一个在多巴胺能神经元中特异性过表达tTA基因的基因敲入小鼠,该小鼠的转基因表达,以及是否受doxycycline的调控将会在以后的工作中继续研究。这一动物模型的建立为研究基因特别是帕金森病相关基因在多巴胺能神经元中的分子通路以及多巴胺能神经元退化提供了一个重要的实验手段。
Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders in the world. It affects about 1% of the population above the age of 60. Clinically, PD is characterized by slowness of movement, rest tremor, rigidity, and disturbances in balance. Pathologically, PD is characterized by the presence of Lewy bodies and selective loss of dopaminergic neuron in the substantia nigra pars compacta (SNc). The dopaminergic neuronal cell death leads to the loss of dopamine (DA) in the striatum and in the SNc. Recent research has enhanced our understanding in PD and this will certainly improve the approaches that can be used in the treatment of PD. Advances in human genetics have enabled us to identify genes that are linked to rare forms of familial PD. DJ-1 is the third gene discovered that to be linked to familial Parkinson's disease by linkage analysis in 2003. These important findings serve as the foundation for discovering new pathways that may lead to the development of new therapies for PD.
DJ-1 belongs to the ThiJ/PfpI superfamily and is well conserved among species. Human DJ-1 coding region consists of 567 nucleotides and encodes a 20kd protein. Mouse DJ-1 shares 90% amino acid homology with human DJ-1. DJ-1 deficient mice are fertile and viable, They display mild movement impairment, dopaminergic dysfunction without dopamine neuron degeneration. The molecular mechanism for DJ-1 mutation related familial Parkinson's disease is still unknown. Several studies suggested DJ-1 may be involved in mitochondria, oxidative sensoring, ubiquitin proteasome system and post-transcriptional regulation control. Moreover, DJ-1, initially discovered as an oncogene and oxidative stress sensor, is increased in serum and cerebrospinal fluid (CSF) of several types of cancers and neurological disorders and might be a novel biomarker for these disease conditions. Northern blot showed DJ-1 mRNA present in all tissues examined, suggesting ubiquitous function of DJ-1. Several studies have examined the expression pattern of DJ-1 in brains of both human and rodents. Surprisingly, these studies generated considerably conflicting results. The major controversy is whether DJ-1 is expressed in neurons or astrocytes and whether DJ-1 is expressed in dopamine neuron. In human brain, it is rather controversial whether DJ-1 is expressed in astrocytes or in neurons. In rodent brains, it is not clear whether DJ-1 is expressed in dopamine neuron in substantia nigra.
Using DJ-1 deficient mouse as negative control, we examined DJ-1 mRNA expression in mouse brains. By sequential double labeling on the same sections, in situ hybridization of DJ-1 mRNA was followed by immunofluorescence detection for TH, NeuN and GFAP. We found DJ-1 mRNA was expressed by greater than 96% neurons but undetectable in astrocytes in most brain regions. All dopamine neurons in ventral midbrain expressed DJ-1 mRNA. Interestingly, choroid plexus and ependymal cells lining ventricles strongly expressed DJ-1 mRNA. The ubiquitous neuronal expression of DJ-1 suggests its fundamental roles underlying neuronal functions. By immunohistochemistry, we found DJ-1 protein is not co-localized with astrocytes. To our surprise, DJ-1 protein is not colocalized with neurons, and the DJ-1 staining is diffused in mouse brain, we then proposed that DJ-1 is axonal transported and secreted by neurons. By colchicine treatment, CSF, and primary neuron culture experiments, we confirmed our hypothesis.
Molecular and genetic studies have made significant progress in revealing protective or risk factors for dopamine neuron survival and dysfunction in Parkinson's disease. However, there is no good genetic approach for high level gene expression in dopamine neuron to test their biological significance in living animals. To overexpress transgene in dopamine neurons, we propose to gene target (knockin) "positive-feedback cassette" into endogenous locus of dopamine transporter (DAT). Positive-feedback cassette will serve as an amplifier to boost transgene expression using bi-directional tetO promoter and DAT locus will favor transgene expression in dopamine neuron. We expect this unique "in situ amplifier" design will achieve doxycycline regulated transgene overexpression specifically in dopamine neurons. The proposed project aims to lay the groundwork for making regulatable tissue specific transgenic overexpression models for future projects in our lab as well as for the entire scientific community.
We constructed ES cell targeting vector, successfully performed ES cell targeting and identified positive targeted ES clones with high targeting efficiency. The identified positive clones were re-amplified and confirmed by southern blot with both 5'and 3'probes. Microinjection is done after we prepared the positive ES cell clones. Chimera mice was got, and we then crossed with C57BL/6 mice, the heterozygous mice with agouti fur will be used to characterize tTA expression pattern and characterize the time course of transgene expression induction by dietary doxycycline in the future.
In summary, we found DJ-1mRNA was expressed by greater than 96% neurons but undetectable in astrocytes in most brain regions. All dopamine neurons in ventral midbrain expressed DJ-1 mRNA. DJ-1 is axonal transported and secreted by neurons.And we generated a knockin mice, the expression pattern of tTA and ChR2-mCherry selectively in dopamine neurons via regulated expression will be done in the future.
引文
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2. Taira, T., et al., Molecular cloning of human and mouse DJ-1 genes and identification of Spl-dependent activation of the human DJ-1 promoter. Gene, 2001.263(1-2):p.285-92.
3. Nagakubo, D., et al., DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun,1997.231(2):p. 509-13.
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