DMRT1 in Mammalian Sexual Development

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 DESCRIPTION (provided by applicant): The overall objective of the proposed work is to understand how the Dmrt1 gene controls cell fates in the mammalian gonad. The testis has two essential functions: production of sperm, the cells that serve as vehicles for the immortality of male germ line DNA; and production of hormones that direct other parts of the body to develop in a male-specific manner. Failures of these processes cause disorders of sex development (DSD), infertility, and gonadal cancer. Dmrt1 belongs to family of conserved transcriptional regulators and controls multiple crucial processes in the mammalian testis both in germ cells and somatic cells. A recent discovery is that DMRT1 controls sexual cell fate: loss of DMRT1 in the testes causes sexual transdifferentiation of male somatic cells to their female equivalents, while expression of DMRT1 in the ovary is sufficient to reprogram female somatic cells into their male equivalents, even in adults. The central hypothesis of this proposal is that competing male and female regulatory networks are continuously required to maintain sexual cell fates and to prevent transdifferentiation. This proposal has three aims focused on a deeper understanding of how DMRT1 controls gonadal cell fate. Aim 1 asks how loss of DMRT1 allows a female regulatory network to supplant the one normally maintaining male sex, and asks through what intermediate state transdifferentiating cells transit. The main approaches will be genome-wide analysis of DNA binding by key sexual regulatory proteins, and transcriptome analysis of transdifferentiating cells. Aim 2 seeks a deeper mechanistic understanding of how DMRT1 regulates target gene transcription to control cell fate and asks how DMRT1 and the conserved male regulator SOX9 functionally interact in this process. The experiments will employ an array of state-of-the-art genomic tools to find key regulatory targets and learn by what transcriptional mechanisms DMRT1 and SOX9 control them. Aim 3 will determine how a newly discovered human DMRT1 mutation causes dominant male-to-female sex reversal, using a mouse model for human DSD. Sexual transdifferentiation is a recently discovered and still understudied biological process and its molecular basis is highly relevant to other examples of transdifferentiation and reprogramming. The proposed work has direct human health relevance: loss of DMRT1 in humans is associated with DSD including male-to-female sex reversal, as well as infertility and testicular germ cell tumors (TGCTs). As a result, the proposed work will help uncover the molecular pathogenesis of DSD and other disorders of the gonad and will inform studies of cell fate reprogramming.