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

在发育中的大脑中，轴突和树突的引导是由排斥性和吸引力的轴突引导分子如Sema3A （Sema3A）和netrin调节的。Collpapsin response mediator protein （CRMP）最初被认为是一种介导Sema3A的细胞内蛋白。我们发现Sema3A引发轴浆运输，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crmp在体内的作用，我们制造了几只crmp1和其他crmp家族基因缺陷的小鼠，并对这些小鼠进行了表型分析。例如，在crmp1缺陷小鼠中，早期胚胎阶段皮质神经元的细胞迁移被延缓。CRMP1与disable -1 （Dab1）共定位，后者是Reln信号传导的一种衔接蛋白。在Relnrl/rl皮层中，CRMP1和Dab1的表达水平较高，而酪氨酸的磷酸化水平较低。在dab1杂合背景下，crmp1的缺失会导致海马层压的破坏，这是一种类似reeler的表型。CRMP1还参与sema3a诱导的AMPA受体定位和大脑皮层的脊柱发育。在培养的crmp1小鼠皮质神经元中，Sema3A增加突触素I簇的密度和突触后密度-95，但在crmp1缺陷小鼠中，这种增加明显减弱。在我们对秀丽隐杆线虫的研究中，我们发现了几个突变等位基因，这些等位基因表现出网络蛋白/UNC-6的异常定位和轴突引导缺陷。因此，我们得出结论，谷氨酸受体和轴突引导分子定位的调节可能在从细胞迁移到神经网络形成的各种发育过程中发挥重要作用。

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.