DMRT1 in Mammalian Sexual Development

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DESCRIPTION (provided by applicant): We identified the first widely conserved class of sexual regulatory genes, transcription factors related to the Drosophila doublesex gene. These share a unique zinc finger DNA binding domain we named the DM domain. In the current funding cycle we have investigated the function of Dmrt1, a mammalian member of this gene family. Human DMRT1 maps to a short segment on chromosome 9p that is deleted in testis dysgenesis. We showed that a null mutation in murine Dmrt1 causes severe defects in testis differentiation and causes sex reversal on at least one strain background. Our expression studies in other species showed that Dmrt1 is probably required for testis development in all vertebrates, including those with highly diverged sex determination mechanisms. The objective of the work we propose is to elucidate the mechanisms by which Dmrt1 and two related genes control mammalian gonad development, at both the genetic and molecular levels. We have four aims. In Aim 1, we investigate which of the known sexual regulatory genes Dmrt1 controls in the embryonic gonad. We also will test the function of a related gene, Dmrt3. Dmrt3 is expressed in the embryonic testis and its human homologue, like DMRT1, is affected by sex reversing human 9p deletions. In Aim 2 we search for additional targets of Dmrt1 regulation in the testis, and test which are regulated directly. In Aim 3 we investigate how the Dmrt1 protein controls transcription, testing the functional importance of candidate transcriptional coregulators that specifically interact with Dmrt1. In Aim 4, we investigate the role in gonad development of Dmrt5, an ovary-specific gene related to Dmrt1, testing whether it plays a role in females analogous to that of Dmrt1 in males. Our work will help to reveal the molecular basis of mammalian sexual differentiation and to establish a pathway of regulatory genes. This will also advance our understanding of the etiology of human congenital defects in this critical process.