Homeobox genes were originally cloned in Drosophila, where they are known to play essential roles in pattern formation. During the previous funding period the investigator studied four mammalian homeobox genes originally cloned in his laboratory. For each gene developmental expression patterns and DNA sequences were determined. Furthermore, for all four genes knockout mice were made, and for each he proceeded to make double knockout mice, in which a closely related gene was also targeted. The Gsh-1 and Gsh-2 homeobox genes were shown to be of critical importance in the development of the hindbrain, pituitary, hypothalamus and basal ganglia. The experiments described in this proposal are designed to carry our understanding of homeobox gene function to the next level. The three aims are: 1) Extensive molecular marker analysis of the Gsh-1, Gsh-2 and Gsh-1 Gsh2 mutant mice. 2) A structure-function dissection of Gsh-1 and Gsh-2 in transgenics. Knock-in experiments will substitute complete coding sequences and generate homeobox swaps. 3) Identification and characterization of Gsh-1 and Gsh-2 downstream target genes. These proposed experiments will better define the developmental function of Gsh-1 and Gsh-2, characterize structure-function relationships of homeobox genes, and determine molecular mechanisms of action through the identification of regulated downstream target genes. Furthermore, the results will test two distinct models of homeobox function, and will provide a general method for the rapid determination of developmental genetic pathways.
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