The mammalian cerebral cortex is an elaborately organized structure containing a constellation of neuronal and glial cell types arranged in laminae. The long term goal of these studies is to understand the mechanisms that govern how this complex organization arises during the formation of the mammalian visual cortex. The role of lineage-derived information in the determination of cell phenotype and establishment of cortical cytoarchitecture will be investigated using as lineage tracers, recombinant retroviruses, which have inserted into their genome exogenous, easily detectable genes, that can be passed on to all the progeny of an infected progenitor cell. The proposed research will combine retroviral lineage tracers with cell type specific antibodies to distinguish the phenotype and neurotransmitter content of clonally related cells, and video microscopy to image over time identified lineally related cells in living slices of developing telencephalon.
The specific aims are to : (1) Analyze the lineage relationships among the different subtypes of neurons and glia comprising the cortex. The phenotypic composition of clonally related cells in the cortex will be examined following injections of retroviral lineage tracers into the telencephalon of rodent embryos, to determine which cell types originate from a common precursor at different times during development and when decisions about cell commitment are made. 2) Investigate the distribution of clonally related cells in the mature an immature cortex in order to reveal the positional relationships among clonally related cells. To determine whether clonally related neurons travel to the cortical plate aligned with a group of radial glial fibers and the extent to which the progeny of a single progenitor cell disperse, the arrangement of clonally related cells will be compared to the distribution of radial glial fibers. (3) Study the dynamic aspects of stem cell proliferation and cell migration within cultured slices of developing cortex to unequivocally identify the progeny of an identified progenitor cell and their properties. The analysis of cell lineage in the visual cortex will serve as a foundation for the ultimate identification of genes that are differentially expressed as cells become committed to a specific pathway of differentiation. In addition, these studies are important for understanding the cause of congenital malformations of human cerebral cortex, believed to result from abnormal cell proliferation, migration and gene expression.
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