Molecular Mechanisms That Control Neuronal Positioning During Development

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During the development of the mammalian brain the majority of neurons migrate away from their sites of origin to regions where they become integrated into functional networks. A number of genes that regulate discrete migration events have been identified. Failures in neuronal migration can lead to diseases ranging in severity from epilepsy to mental retardation. My lab investigates the genes that encode components of a signaling cascade that regulate neuronal positioning, including an extracellular ligand, Reelin; two receptors, ApoER2 and VLDLR; and a cytoplasmic docking protein, Dab1. This signaling pathway regulates the positioning of neurons in several brain regions including the cerebral cortex, the hippocampus, and the cerebellum. We have worked to extend the understanding of the components of the pathway. We have demonstrated genetic interactions between Dab1 and APP in mouse development, using a hypomorphic Dab1 allele generated in the lab. We found that overexpression of APP lead to a worsening of the Dab1 hypomorphic phenotype. In contrast, loss-of -function APP partially rescued the mild Dab1 phenotype. This provides evidence that the APP gene, which is involved in Alzheimers disease, influences a molecular pathway that controls brain development. We are currently working to determine the molecular mechanism that leads to this genetic interaction. We have examined the role for the Crk family of adaptor proteins in Reelin-regulated neurite extension. Using siRNAs that interfere with the expression of Crk and the relative CrkL we have shown that these molecules are required for Reelin-mediated dendrite extension, but they are not required for axonogenesis. This work demonstrates a role for Crk and CrkL in the Reelin-signaling pathway downstream of Dab1 tyrosine phosphorylation.