Normal development of human cerebral cortex is essential for cognitive function, and is disrupted in many human neurological disorders that are associated with epilepsy, mental retardation, or other learning disorders. The first cycle of this grant used retroviral lineage markers to analyze cell division and neuronal migration in the cerebral cortex. The second cycle of this grant, now ending, continued the cell lineage analysis and examined a few specific genes that regulate cortical patterning and cell fate. These studies have led us to an analysis of the control of the subcellular localization of specific proteins, and studies of their role in controlling cell fate in the developing cerebral cortex. Particular proteins are known to be expressed asymmetrically in dividing cells, and are hence inherited preferentially by one of the two daughter cells of dividing cell. This asymmetric inheritance of protein determinants appears to be an important means of determining cell fate in many species. The first specific aim of this grant proposes to analyze the polarized expression of several protein complexes in developing neuroepithelial cells of the cerebral cortex, in relation to centrosomes. The second specific aim proposes to analyze how these polarized patterns of protein expression influence epithelial polarity and neurogenesis in the cerebral cortex. Finally, the third specific aim analyzes the role of the centrosome in neurogenesis, and the biochemical and functional connection between polarized protein expression and mitotic spindle orientation in the cortical neuroepithelium. ? ?
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