G蛋白偶联受体激酶5在斑马鱼造血系统发育中调节作用的研究
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摘要
G蛋白偶联受体(GPCR)是细胞膜表面最大的一类受体超家族,具有七次跨膜螺旋结构,介导多种多样的配体信号,包括神经递质、激素、气味以及其他小分子等,广泛的参与多种生理功能,同时其自身也受到精细的调节,其中重要的一种负反馈调节即为由G蛋白偶联受体激酶(G protein coupled receptor kinase, GRK)介导的受体脱敏。目前已发现七种GRK亚型：GRK1-7。其分布、作用底物也不尽相同。
造血系统的发育维持受到一系列转录因子的调控,GATA家族是其中一类重要的转录因子,GATA2主要分布在造血干细胞和前体细胞中,对造血系统的发育有重要的调节作用。结合本实验室以及最新的的研究报道提示,斑马鱼GRK2/3可通过与PTCH1的相互作用以及磷酸化Smo等途径在胚胎发育过程中发挥着重要调控作用。本研究在以前工作的基础上,以斑马鱼为模型初步探索了G蛋白偶联受体激酶5对造血系统发育的调控作用及其机制。
本研究结果：(1)我们根据斑马鱼基因库中GRK5的同源序列,通过采用提取斑马鱼总RNA,进行RACE-PCR的方法克隆出了斑马鱼的GRK5,并对其序列进行了进化分析。(2)采取整体原位杂交的实验方法对GRK5在斑马鱼体内的表达分布情况进行了初步探讨。采用morpholino的方法在斑马鱼中对GRK5进行Knockdown之后,造血系统发育必需的标记基因Fli-1以及Gata1的表达量均有明显下降,这种现象能被外转的GRK5全长蛋白以及激酶活性缺失突变体K215R所逆转。提示GRK5可能参与到造血系统的发育调控。(3)通过免疫共沉淀的方法,我们发现GRK5与GATA2存在相互作用,并且GRK5的216位精氨酸在与GATA2发生相互作用中是必需的。(4)在过表达GRK5或者对GRK5进行Knockdown之后采用RT-PCR的实验方法验证造血相关GATA2下游基因包括a-globin、γ-globin、MLF1、P27、PU1的表达均发生明显改变。进一步实验发现GRK5与GATA2相互作用功能缺失突变体GRK5-R216L不能逆转由GRK5的Knockdown引起的斑马鱼造血系统发育必需的标记基因的表达异常。
综上所述,本研究发现(1)GRK5对斑马鱼造血正常发育必需的标记基因Fli-1和Gata-1的正常表达是必需的,提示其可能参与到斑马鱼造血系统发育的调控；(2)GRK5通过与GATA2的相互作用来调节GATA2的转录活性并影响GATA2下游基因表达,这为进一步研究GRK5对斑马鱼造血系统发育的调控机制提供了新的思路。
G protein-coupled receptor (GPCR) family represents the largest class of cell surface receptors with seven transmembrane domains.It can transduce a large number of extracellular signals including hormones, neurotransmitters, chemokins and other environmental stimuli to the intracellular compartment. Widely involved in various physiological functions, itself is regulated exquisitly through a variety of ways, such as GPCR desensitization through G protein-coupled receptor kinase(GRK)catalyzing the phosphorylation of agonist-occupied GPCR. Seven different members of GRKs have been found for now:GRK1-7.Their distribution and substrate are not very similar.
Hematopoietic system development is controled by a series of transcription factors, GATA family transcription factors play key roles in this process.GATA2 is expressed at the stem and progenitor stage, including erythroid lineage, in hematopoiesis, is essential for hematopoietic system development. Studies of our lab and the new researchs have shown that GRKs play an important role in zebrafish embryo development through interaction with PTCH1 and phorphorylating Smo.In this study, on the basis of previous work, taking zebrafish as a research model, we initially explored the role of G protein-coupled receptor kinase 5 on the regulation of hematopoietic system development and its mechanism.
Our results show that:(1)Based on the GRK5 homologous sequences in zebrafish gene pool, we extracted zebrafish total RNA and cloned the full-length sequence of zebrafish GRK5 utilizing RACE-PCR method. (2) We taked a preliminary study of GRK5's distribution in zebrafish through Whole-mount In Situ Hybridization. Knockdown GRK5 in zebrafish through morpholino reduced the expression of Fli-1,Gata1--two transcription factors related to hematopoietic system development, this down-expression can be rescued by GRK5 and GRK5-K215R. This results indicate that GRK5 may play roles in hematopoiesis.(3)We initialy found the interaction between GRK5 and GATA2 by coimmunoprecipitation approach, and the 216 arginine of GRK5 is essential to this interaction. (4) We overexpressed GRK5 or knockdown GRK5 in K562 cells and then screened the GATA2 downstream genes related to hematopoietic system utilizing Real Time PCR, found that the expression of a-globin,γ-globin, MLF1, P27 and PU.1 is changed obviously. Further experiments found that GRK5 mutant R216L can not rescue the down-expression of mark gene related to hematopoiesis by knockdown of GRK5 in zebrafish.
In conclusion, our researchs indicate that(1)GRK5 is required for the normal expression of marker genes related to zebrafish hematopoietic development, indicating that GRK5 is required for hematopoiesis.(2) GRK5 interacts with GATA2 and regulates the expression of GATA2 downstream genes through interaction with GATA2, this results provide a new idea for further research of the regulation mechanism of GRK5 on the development of zebrafish hematopoiesis.
造血系统的发育维持受到一系列转录因子的调控,GATA家族是其中一类重要的转录因子,GATA2主要分布在造血干细胞和前体细胞中,对造血系统的发育有重要的调节作用。结合本实验室以及最新的的研究报道提示,斑马鱼GRK2/3可通过与PTCH1的相互作用以及磷酸化Smo等途径在胚胎发育过程中发挥着重要调控作用。本研究在以前工作的基础上,以斑马鱼为模型初步探索了G蛋白偶联受体激酶5对造血系统发育的调控作用及其机制。
本研究结果：(1)我们根据斑马鱼基因库中GRK5的同源序列,通过采用提取斑马鱼总RNA,进行RACE-PCR的方法克隆出了斑马鱼的GRK5,并对其序列进行了进化分析。(2)采取整体原位杂交的实验方法对GRK5在斑马鱼体内的表达分布情况进行了初步探讨。采用morpholino的方法在斑马鱼中对GRK5进行Knockdown之后,造血系统发育必需的标记基因Fli-1以及Gata1的表达量均有明显下降,这种现象能被外转的GRK5全长蛋白以及激酶活性缺失突变体K215R所逆转。提示GRK5可能参与到造血系统的发育调控。(3)通过免疫共沉淀的方法,我们发现GRK5与GATA2存在相互作用,并且GRK5的216位精氨酸在与GATA2发生相互作用中是必需的。(4)在过表达GRK5或者对GRK5进行Knockdown之后采用RT-PCR的实验方法验证造血相关GATA2下游基因包括a-globin、γ-globin、MLF1、P27、PU1的表达均发生明显改变。进一步实验发现GRK5与GATA2相互作用功能缺失突变体GRK5-R216L不能逆转由GRK5的Knockdown引起的斑马鱼造血系统发育必需的标记基因的表达异常。
综上所述,本研究发现(1)GRK5对斑马鱼造血正常发育必需的标记基因Fli-1和Gata-1的正常表达是必需的,提示其可能参与到斑马鱼造血系统发育的调控；(2)GRK5通过与GATA2的相互作用来调节GATA2的转录活性并影响GATA2下游基因表达,这为进一步研究GRK5对斑马鱼造血系统发育的调控机制提供了新的思路。
G protein-coupled receptor (GPCR) family represents the largest class of cell surface receptors with seven transmembrane domains.It can transduce a large number of extracellular signals including hormones, neurotransmitters, chemokins and other environmental stimuli to the intracellular compartment. Widely involved in various physiological functions, itself is regulated exquisitly through a variety of ways, such as GPCR desensitization through G protein-coupled receptor kinase(GRK)catalyzing the phosphorylation of agonist-occupied GPCR. Seven different members of GRKs have been found for now:GRK1-7.Their distribution and substrate are not very similar.
Hematopoietic system development is controled by a series of transcription factors, GATA family transcription factors play key roles in this process.GATA2 is expressed at the stem and progenitor stage, including erythroid lineage, in hematopoiesis, is essential for hematopoietic system development. Studies of our lab and the new researchs have shown that GRKs play an important role in zebrafish embryo development through interaction with PTCH1 and phorphorylating Smo.In this study, on the basis of previous work, taking zebrafish as a research model, we initially explored the role of G protein-coupled receptor kinase 5 on the regulation of hematopoietic system development and its mechanism.
Our results show that:(1)Based on the GRK5 homologous sequences in zebrafish gene pool, we extracted zebrafish total RNA and cloned the full-length sequence of zebrafish GRK5 utilizing RACE-PCR method. (2) We taked a preliminary study of GRK5's distribution in zebrafish through Whole-mount In Situ Hybridization. Knockdown GRK5 in zebrafish through morpholino reduced the expression of Fli-1,Gata1--two transcription factors related to hematopoietic system development, this down-expression can be rescued by GRK5 and GRK5-K215R. This results indicate that GRK5 may play roles in hematopoiesis.(3)We initialy found the interaction between GRK5 and GATA2 by coimmunoprecipitation approach, and the 216 arginine of GRK5 is essential to this interaction. (4) We overexpressed GRK5 or knockdown GRK5 in K562 cells and then screened the GATA2 downstream genes related to hematopoietic system utilizing Real Time PCR, found that the expression of a-globin,γ-globin, MLF1, P27 and PU.1 is changed obviously. Further experiments found that GRK5 mutant R216L can not rescue the down-expression of mark gene related to hematopoiesis by knockdown of GRK5 in zebrafish.
In conclusion, our researchs indicate that(1)GRK5 is required for the normal expression of marker genes related to zebrafish hematopoietic development, indicating that GRK5 is required for hematopoiesis.(2) GRK5 interacts with GATA2 and regulates the expression of GATA2 downstream genes through interaction with GATA2, this results provide a new idea for further research of the regulation mechanism of GRK5 on the development of zebrafish hematopoiesis.
引文
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