MOLECULAR NEUROGENESIS

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Molecular neurogenesis in Xenopus will be studied by examining the function of the Xotch and X-ASC 108 genes. These are genes represented by cDNAs we have isolated by homology to Drosophila genes that are clearly involved in neurogenesis. Our long term goal is to begin to understand which genes are critical for neuronal determination and differentiation in the vertebrate CNS. These two sets of genes we have recently isolated and characterized represent a significant possibility for a first step in that direction. With respect to Xotch, we propose to first make antibodies to the Xotch protein. We will use these antibodies to study the expression of the protein and in separate experiments to perturb Xotch function. Our hypothesis is that Xotch is critical for the cell-cell interactions that generate cell-type diversity in the retina. We will also try to interfere with Xotch function through the genetically engineered construction of antisense oligonucleotides or dominant-negative mutants which can be overexpressed in cells to interfere with normal Xotch function. The ASC genes of Drosophila are thought to act as nuclear regulators of neuronal differentiation. We propose first to use sequence analysis to determine whether our X-ASC clones are true homologs of the Drosophila transcripts. We then will study the expression pattern of the different X- ASC clones to find ones that are most likely to have a neurogenic function. Finally, we will design molecular inhibitors of X-ASC to assay the function of these genes in neural development.