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The role of CRMP family proteins in the establishment of neural tissue architectures

CRMP 家族蛋白在神经组织结构建立中的作用

基本信息

批准号：
17082006
负责人：
GOSHIMA Yoshio
金额：
$ 65.09万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2009
项目状态：
已结题

项目摘要

In developing brain, axon and dendritic guidance are regulated by repulsive and attractive axon guidance molecules such as semaphorin3A (Sema3A) and netrin. Collpapsin response mediator protein (CRMP) has originally been identified as an intracellular protein that mediates Sema3A. We found that Sema3A elicits axoplasmic transport that may be involved in regulating the localization of AMPA type glutamate receptors in hippocampal neurons. To elucidate in vivo role of CRMPs, we generated several crmp1 and other crmp family gene-deficient mice and performed phenotypic analysis of these mice. For instance, in crmp1-deficient mice, the cell migration of cortical neurons at early embryonic stages is retarded. CRMP1 is colocalized with disabled-1 (Dab1), an adaptor protein in Reln signaling. In the Relnrl/rl cortex, CRMP1 and Dab1 are expressed at a higher level, yet tyrosine phosphorylated at a lower level. Loss of crmp1 in a dab1 heterozygous background lead to the disruption of hippocampal lamination, a Reeler-like phenotype. CRMP1 is also involved in Sema3A-induced localization of AMPA receptors and spine development in the cerebral cortex. In the cultured cortical neurons from crmp1 mice, Sema3A increases the density of clusters of synapsin I and postsynaptic density-95, but this increase is markedly attenuated in crmp1-deficient mice. In our study of C. elegans, we identified several mutant alleles which show aberrant localization of netrin/UNC-6 and axon guidance defects. We therefore conclude that the regulation of the glutamate receptor and the axon guidance molecule localization may play an important role in a wide variety of developmental processes from cell migration to neural network formation.

在发育中的大脑中，轴突和树突的导向受到排斥性和吸引性轴突导向分子如semaphorin 3A（Sema 3A）和netrin的调节。胶原蛋白酶反应介导蛋白（CRMP）最初被鉴定为介导Sema 3A的细胞内蛋白。我们发现Sema 3A介导的轴浆转运可能参与调节海马神经元AMPA型谷氨酸受体的定位。为了阐明CRMPs在体内的作用，我们产生了几个crmp 1和其他crmp家族基因缺陷小鼠，并对这些小鼠进行表型分析。例如，在crmp 1缺陷小鼠中，胚胎早期皮层神经元的细胞迁移被延迟。CRMP 1与Reln信号传导中的衔接蛋白disabled-1（Dab 1）共定位。在Relnrl/rl皮质中，CRMP 1和Dab 1以较高水平表达，但酪氨酸磷酸化水平较低。dab 1杂合子背景中crmp 1的缺失导致海马分层的破坏，这是一种Reeller样表型。CRMP 1还参与Sema 3A诱导的AMPA受体定位和大脑皮层中的脊柱发育。在培养的皮层神经元crmp 1小鼠，Sema 3A增加突触蛋白I和突触后密度-95的集群的密度，但这种增加显着衰减crmp 1缺陷小鼠。在我们对C.在elegans中，我们鉴定了几个突变等位基因，其显示netrin/β-6的异常定位和轴突引导缺陷。因此，我们得出结论，谷氨酸受体和轴突导向分子的本地化的调节可能发挥了重要作用，在各种各样的发展过程中，从细胞迁移到神经网络的形成。