The proposal aims to identify and characterize components of the signaling pathways required for neuronal migration and cortical development. Although defects in Dbcn, mDab1, and beta LIS1 all lead to severe cortical abnormalities, little is known about the signaling pathways in which these gene products participate. Especially little is known about Dbcn, discovered earlier this year by Walsh and his colleagues.
Aim 1 proposes to identify functionally important domains of the Dbcn protein by screening for additional XLIS/double cortex mutations.
In aim 2 the distribution of Dbcn mRNA and protein will be determined, an essential first step to investigate the possible roles of Dbcn. Although database searches reveal few other proteins similar to Dbcn, an uncharacterized protein from brain known as KIAA0369 has an N-terminal domain that shares ~75% identity to Dbcn and a C-terminal domain that shares 97% identity with a cam kinase. Given the striking similarity between KIAA0369 and Dbcn and the possibility that they have similar (or competing) functions, the localization of KIAA0369 relative to Dbcn will be determined. The phenotypic similarity of mutants in Dbcn, mDab, and beta LIS1 suggests the hypothesis that these genes may function in the same critical signaling pathway. The possibility that these proteins interact directly with one another will be tested in aim 3 using immunoprecipitations and pair-wise two-hybrid assays and immunoprecipitation assays. Non-receptor tyrosine kinases such as Abl are likely to be involved in the pathways underlying cortical migration, and Walsh et al. have identified a putative Abl phosphorylation site in Dbcn. The predicted structure of Disabled as an adapter protein for non-receptor tyrosine kinases such as Abl also supports the hypothesis that non-receptor tyrosine kinases are important components of these pathways.
Thus aim 3 will include studies to determine if Dbcn is a substrate for Abl and whether Abl interacts with mDab1 or beta LIS1. The final component of this proposal (aim 4) is to perform an extensive series of two-hybrid screens with Dbcn, mDab1, and beta LIS1 to screen for interacting proteins. Any proteins that are identified as interacting will be tested for binding in biochemical assays and would be candidate genes for lissencephaly.
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