In the developing mammalian brain, directed cell migrations establish the neuronal layers of the cerebellum and the neocortex. While a number of receptor systems have been studied in vertebrate neuronal migrations, an important avenue of discovery of genes that potentially regulate CNS migrations is to search for homologues of genes that function in neuroblast migration in C. elegans and Drosophila. During the prior funding period of this grant, we have begun studies with the laboratory of Dr. Cynthia Kenyon to explore the role of homologues of C. elegans neuroblast migration genes in mammalian brain development. Toward that end, we have cloned homologues of the C. elegans gene mig-13 and initiated studies on the role of Mmig13 in brain development. The overall goal of this Research Plan is to define the function of murine homologues of the C. elegans gene mig-13 in the formation of murine cerebellar and neocortical neural laminae. Our preliminary studies suggest that Mmig13 functions in the formation of the EGL in the embryonic cerebellar anlagen, prior to migration of postmitotic precursors along the Bergmann glial fibers, and in the formation of the cortical plate, the region where young neurons in the neocortex halt their movements along radial glial fibers and assemble into specific layers. The proposed research is aimed at testing and refining this general hypothesis by providing more detailed studies on the timing of expression of Mmig13 in these two brain structures, by imaging living neurons in cells and tissue from Mmig13 BAC transgenic mice, where the Mmig13 gene is marked by EGFP, and by evaluating the effects of either gain of function or loss of function on granule cell migration and/or cortical neuron migration. To better understand the mechanism of action of the gene(s), we will define their extracellular ligands and their intracellular signaling pathways. This information should broaden our view of the mechanisms that control CNS migrations and of the downstream events important to neuronal differentiation within the neural layers.
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