reproduced verbatim): The goals of this proposal are to understand how posterior regions of the nervous system (hindbrain and spinal cord) are initially determined in vertebrates, using the zebrafish as a paradigm. The zebrafish is a wonderful model, allowing analysis of the early, crucial stages of nervous system development, by both embryological and genetic analysis. Integral to this study is a set of genes that we isolated by subtractive cloning, and that is expressed exclusively in the posterior of the embryo during gastrulation, when neural patterning has begun but before neural differentiation has occurred. Some of the genes isolated contain DNA binding motifs, while some are novel, suggesting that we have enriched for regulatory genes. This application has three parts. First, using these genes as markers, the tissues responsible for posterior neural induction will be determined, using explant assays that were developed for zebrafish in my laboratory. Second, the factors required for induction of posterior neural tissue will be analyzed using zebrafish mutants and dominant negative proteins. Third, the function of a subset of genes isolated by subtraction will be addressed. Genes will be placed on the zebrafish genetic map to determine whether they correspond to known mutations. Gain of function assays will ask how the novel nlz gene modulated posterior neural patterning. This application will define the cell interactions and genes required for normal hindbrain and spinal cord development. Normal brain development and health require integration of all parts of the nervous system, suggesting that deficits in the posterior nervous system may contribute to or exacerbate malfunction of other brain regions. The genes to be studied here may also help define the genetic basis of neural tube birth defects.
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