CNS DEVELOPMENT AND MUTANT GENE ACTION

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The genetic and epigenetic mechanisms by which the brain develops into a highly ordered structure are largely unknown. The goal of this proposal is to elucidate some of the early postmitotic events in neurogenesis. There are several neurological mouse mutants which are defective in particular aspects of this developmental program. Two such genetic mutants, the weaver (wv) and the reeler (rl), hold forth fascinating information concerning the genetic control over the migratory phase of neurogenesis. These mutations affect the ability of a single cell type (the wv cerebellar granule cells) or virtually all cell types (rl) to migrate and stabilize appropriately. Experimental mouse chimeras provide a direct means to ascertain the target(s) of mutant gene action. Four cell embryos of normal (Mus caroli) and neurological mutant (Mus musculus) mice will be aggregated to form a single chimeric embryo composed of genetically normal and mutant cells. A new cell marking system will be used to identify each cell of the chimeric brain, as genotypically normal or mutant. This new cell marker, which involves the in situ hybridization of a species-specific cDNA probe to mark Mus musculus but not Mus caroli cells, will permit careful light and electron microscopic analyses of each cell's genotype compared to its phenotype. The genotype/phenotype comparisons will define the intrinsic or extrinsic nature of wv and rl mutant gene action relative to all cell types in the cerebellum. This type of information will provide a better understanding of normal brain development and how abnormal development occurs at both the more obvious (e.g., congenital ataxias) and more subtle (e.g., mental retardation) levels of dysgenesis.