The objective of this program is to identify and functionally characterize neurogenic genes that are required for CNS development. Given the high degree of conservation in basic developmental mechanisms used by all metazoans, we have focused our efforts on the study of CNS development in the fruit fly (Drosophila melanogaster) where the genetic information required for these events is accessible. Using classical genetic, molecular biology and transgenic techniques, we have continued to study the function of genes expressed during neuroblast lineage differentiation. Thus far, our study of castor, a novel Zinc finger gene required for proper CNS neuroblast development, has revealed that it encodes a nuclear located, sequence-specific DNA-binding protein whose expression is restricted to late forming CNS neuronal precursor lineages. We hypothesize that castor protein functions as a transcription factor required for the correct regulation of genes in these lineages. Our recent studies have shown that castor controls cell fate decisions by regulating the expression of known CNS cell fate determinant transcription factors (pdm-1, -2 and drifter). While castor is required for the silencing of both pdm-1 and -2 gene expression (early lineage determinants), drifter requires castor for its proper expression. A search for additional regulatory targets of castor has identified in vivo DNA-binding sites that are positioned adjacent to genes expressed during CNS development. Recent analysis of one of these targets, the heat-shock gene, hsp-27, has shown that, in the absence of heat induction, castor function is necessary for its proper expression in a subset of late forming neuroblast lineages. We have also continued our characterization of castor cognate genes in other diptera. Information obtained from these comparisons will aid in our identifying mammalian cognates. Our continued analysis of pollux a membrane associated adhesion protein encoding gene has revealed that it contains a highly conserved 74 amino acid protein domain that is found in plant and human proteins. We hypothesize that this adhesion molecule plays a role in both the maintenance of CNS axon fascicles and in proper trachea function. We have also continued our functional analysis of the murine homeobox gene A5. Ectopic expression of A5 in transgenic mice correlates with the apparent repression of a hepatocyte nuclear transcription factor (HNF-3 beta) in adult tissues and in skeletal malformations during development.
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