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

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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.