The purpose of the research in this proposal is to study the tissue- specific regulation of the Deformed (Dfd) gene and its vertebrate homologues during the development of the nervous system. The laboratory research will be performed in conjunction with a didactic program guided by the sponsor and a review committee. Through this plan, the candidate will develop the technical expertise, fundamental knowledge, and intellectual scientific approach necessary for an independent and productive career in the molecular study of development. Phase 1 of this proposal will include formal coursework and seminars, as well as the first part of the proposed research, under the close supervision of Dr. William McGinnis. Phase 2 will be characterized by a continuation of the outlined laboratory investigations on a more independent level, and collaboration with Dr. Frank Ruddle for the detailed development and execution of the vertebrate studies. The research goals will be carried out by a combination of molecular, biochemical, genetic, and transgenic approaches. The project focuses on Dfd, a homeobox-containing homeotic selector gene that determines head- specific fates in the Drosophila embryo. A recently identified regulatory element from the Dfd locus specifies expression of a reporter gene in a subset of the normal Dfd pattern, including part of the central nervous system, the subesophageal ganglion. This element will be characterized and compared to another Dfd regulatory region (an epidermal enhancer) by cross-hybridization and sequence comparison. Genetic crosses will be used to understand the regulation of these elements by candidate genes, including Dfd itself. And rescue of Dfd null flies will be attempted with the Dfd cDNA. A regulatory region from a human Dfd cognate gene directs expression in the nervous system of transgenic mice. This vertebrate control element will be compared with the Drosophila Dfd neural-specific element in biochemical and functional tests, including transgenic mouse studies, to determine what is important for regulatory function in these evolutionarily conserved genes from such highly diverged sources.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Physician Scientist Award (K11)
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Maternal and Child Health Research Committee (HDMC)
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Yale University
Schools of Medicine
New Haven
United States
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Bogue, C W; Lou, L J; Vasavada, H et al. (1996) Expression of Hoxb genes in the developing mouse foregut and lung. Am J Respir Cell Mol Biol 15:163-71
Lou, L; Bergson, C; McGinnis, W (1995) Deformed expression in the Drosophila central nervous system is controlled by an autoactivated intronic enhancer. Nucleic Acids Res 23:3481-7