Classical lissencephaly is a human neurological disorder characterized by an abnormality in neuronal migration. Individuals who have this disorder are profoundly retarded and often develop seizures. The most frequent genetic abnormality that causes this disorder involves a deletion in one allele of the LIS1 gene on chromosome 17. This gene was isolated several years ago by various members of the Program Project team. More recently, a second gene that causes a similar neuronal migration abnormality has been identified. This gene, called doublecortin, lies on the X chromosome. The proposed research will determine the function of the protein encoded by LIS1, termed betaLIS1, as well as the function of the protein encoded by doublecortin. It is anticipated that the proposed studies will lead to a better understanding of the function of betaLIS1 and doublecortin in normal neuronal migration, and in the pathogenesis of neuronal migration disorders. The Lis1 gene product has been shown to be a component of platelet-activating factor acetylhydrolase, or PAFAH (Ib). The latter is a complex that contains not only the protein encoded by LIS1, but also 2 additional proteins. The three proteins have been suggested to form a G-protein like heterotrimer. It has been suggested that the intact PAFAH (Ib) complex binds to PAF, hydrolyzes it, and thereby inactivates this potent second messenger. The exact function of betaLIS1 in this signaling process is not known. betaLIS1 shares homology with fungal and yeast proteins. These homologies suggest that the function of betaLIS1 is that of a signaling molecule that is involved in the regulation of the microtubule-based motor dynein. The proposed research will test the hypothesis that the function of betaLIS1 in neuronal migration is that of a signaling molecule acting within the neuron that is migrating, to convey signaling from the binding of PAF to the a subunits of PAFAH (Ib). This interaction will lead to the activation of dynein. The proposed experiments will be performed in mouse cerebellar granule cell cultures that will be derived from wild type and betaLIS1 deficient mice. This will allow for the comparison of nearly pure neuronal populations that are capable of neuronal migration in vitro. The initial series of experiments will determine differences in the ability of these neurons to migrate. Utilizing a PAF induced neurite retraction assay and dynein microtubule gliding assays, it will be demonstrated that PAF signaling in developing neurons involves PAFAH (Ib) and dynein. The regulation of betaLIS1 by doublecortin will be investigated.
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