Genetic Analysis of Morphogenesis in a Nematode

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DESCRIPTION (provided by applicant): This research concerns how the differentiated cells of the body are produced during animal development. Each differentiated cell expresses a characteristic set of genes as a result of a cell fate specification process that takes place during embryonic and postembryonic development. Precisely regulated activation of genes encoding cell fate determining transcription factors is critical to the orderly cell fate specification process. The aim of this research is to understand how transcriptional activation of one such cell fate determining transcription factor gene is specified to occur in a particular cell and at a particular time during development. The gene to be studied is egl-5, a member of the Hox gene family of the nematode Caenorhabditis elegans, a model organism for developmental studies. egl-5 determines cell fates in a postembryonic cell lineage that gives rise to sensory structures of the adult male tail. The transcription factors that activate a cell-specific cis-regulatory element from the egl-5 promoter will be identified. One key activator is another Hox protein MAB-5, which may interact directly with the cis-regulatory element; thus, this research serves as a model to understand a lox gene cascade. MAB-5 activity is regulated by additional factors, which will be identified. As is typical for Hox genes, egl-5 is activated by a combination of both positive and negative pathways. A factor or factors that bind to a negative regulatory site within the cis-regulatory element will be identified and characterized. Genes acting in a global Hox gene regulatory pathway will be isolated and the functions of their products analyzed. Further experiments will determine how the activities of transcriptional activators and repressors of the cis-regulatory element are controlled by developmental timing genes. This research will contribute to understanding a fundamental aspect of animal development, and thus help towards progress in overcoming diseases that arise as a result of developmental abnormalities.