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Functional analysis of the scaffold protein JSAP1 in the developing mouse cerebellum

小鼠小脑发育中支架蛋白JSAP1的功能分析

基本信息

批准号：
18500238
负责人：
YOSHIOKA Katsuji
金额：
$ 2.57万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18500238/
关键词：
cadherin cerebellum development and differentiation genetically engineered mice JNK MAP kinase scaffold protein signal transduction

项目摘要

Scaffold proteins of the mammalian MAP kinase (MAPK) cascades are thought to function in the spatio-temporal regulation of these pathways by organizing the signaling components into functional modules. We have examined the functions of c-Jun NH,-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), a scaffold protein that are involved in INK MAPK cascades. Our findings are summarized as follows:1) We first generated genetically engineered mice carrying a lox-P-flanked (foxed) Jsap 1 gene, and introduced the foxed Jsap 1 deletion mutant specifically into the neural lineage. The Jsap 1 conditional knockout mice showed essentially the same phenotypes as the JSAP1-null mice, suggesting that the neonatal death of Jsap 1-deficient mice is caused by defects in the nervous system (Neurosci. Lett., 2007).2) We showed that JSAP1 scaffold regulates cell-cell interactions in PC12h cells specifically in the NGF-induced signaling pathway, and does so by modulating N-cad … More herin (Biochem. Biophys. Res. Commun., 2007) through the knock down experiments in PC12h cells.3) We also studied JSAP1 and JNK expression in mouse brains. Our results obtained by in situ hybridization and immunohistochemical analyses strongly suggested that JSAP1-JNK signaling plays important roles in developing and adult mouse brains (J. Neurothem., 2006).4) During the development of the cerebellum, massive clonal expansion of granule cell precursors (GCPs) occurs in the outer part of the external granular layer (EGL). We have provided evidence that JSAP1 and active JNK were expressed preferentially in the post-mitotic inner EGL progenitors in the developing cerebellum. Moreover, Jsap 1 deficiency resulted in increasing numbers of proliferating GCPs in mouse embryos. Besides, overexpression of JSAP1 in cultured GCPs led to increased numbers of NeuN-positive cells together with the activation of JNK. Together, these data strongly indicated that JSAP1 promotes the cell-cycle exit and differentiation of GCPs by modulating JNK activity in cerebellar development (in preparation). Less

哺乳动物MAP激酶（MAPK）级联的支架蛋白被认为通过将信号组件组织成功能模块，在这些通路的时空调节中起作用。我们研究了c-Jun NH，末端激酶(JNK)/应激激活蛋白激酶相关蛋白1 （JSAP1）的功能，这是一种参与INK MAPK级联反应的支架蛋白。本研究的主要成果如下：1)首先构建了携带ox- p -flanked (foxed) Jsap 1基因的基因工程小鼠，并将foxed Jsap 1缺失突变体特异性导入神经谱系。Jsap 1条件敲除小鼠的表型与jsap1缺失小鼠基本相同，这表明Jsap 1缺失小鼠的新生儿死亡是由神经系统缺陷引起的(神经科学。列托人。, 2007)。2)我们发现，在ngf诱导的信号通路中，JSAP1支架通过调节N-cad来调节PC12h细胞中细胞间的相互作用。Biophys。Commun >,， 2007)通过敲低PC12h细胞的实验。3)我们还研究了JSAP1和JNK在小鼠脑中的表达。我们通过原位杂交和免疫组织化学分析获得的结果强烈表明，JSAP1-JNK信号在发育和成年小鼠大脑中起重要作用（J. Neurothem.）。, 2006)。4)在小脑发育过程中，颗粒细胞前体（GCPs）大量克隆扩增发生在外颗粒层（EGL）的外层。我们提供的证据表明，在发育中的小脑中，JSAP1和活性JNK在有丝分裂后的EGL内祖细胞中优先表达。此外，Jsap 1缺乏导致小鼠胚胎中增殖gcp数量增加。此外，在培养的GCPs中，过表达JSAP1导致neun阳性细胞数量增加，JNK激活。总之，这些数据强烈表明，JSAP1通过调节小脑发育过程中的JNK活性，促进GCPs的细胞周期退出和分化。少