The overall objective of the proposed work is to understand how the Dmrt1 gene controls development and function of the testis. 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. Dmrt1 belongs to family of conserved transcriptional regulators and controls multiple critical processes in the mammalian testis. This work has direct human health relevance: loss of DMRT1 in humans is associated with male-to-female sex reversal, disorders of sexual differentiation (DSD), infertility, and testicular germ cell tumors (TGCTs). In mice Dmrt1 controls germ cell pluripotency in the fetal gonad and controls the mitosis/meiosis decision in adults. A new discovery is that testis determination must be actively maintained postnatally by Dmrt1 and that Dmrt1 mutant testes undergo massive postnatal reprogramming to become ovary-like organs. This proposal has three aims focused on deepening our understanding of how DMRT1 controls key processes in the testis.
Aim 1 asks how DMRT1 prevents transdifferentiation in the postnatal testis. This is a newly discovered and unstudied biological process. The proposed experiments use conditional gene targeting approaches to ask whether DMRT1 prevents reactivation of the fetal sex determination network postnatally, identify new regulators of postnatal sex maintenance, and use ChIP-seq to identify genes that are bound by DMRT1 in the mouse and human testis.
Aim 2 tests the hypothesis that DMRT1 is critical for the transition from spermatogonia stem cell to committed progenitor cell, using precisely controlled loss- and gain-of-function approaches.
Aim 3 will determine how DMRT1 is inactivated as spermatogonia transition from mitosis to meiosis and will test the consequences when this fails to occur. The results of this study should aid in treatment of gonadal cancer and infertility, and will inform studies of cell fate reprogramming and design of novel male contraceptives.
The proposed work is highly relevant to human health. DMRT1 is implicated in human infertility, testicular dysgenesis, and testicular cancer and the proposed studies may permit better diagnosis and treatment of these conditions. Furthermore, because this work focuses on cell fate reprogramming, regulation of germ line stem cells, and control of the mitosis/meiosis decision, the resulting data may aid in stem cell therapy, direct reprogramming of cell fate, infertility treatment, and contraception.
|Zhang, Teng; Zarkower, David (2017) DMRT proteins and coordination of mammalian spermatogenesis. Stem Cell Res 24:195-202|
|Nakagawa, Tadashi; Zhang, Teng; Kushi, Ryo et al. (2017) Regulation of mitosis-meiosis transition by the ubiquitin ligase ?-TrCP in male germ cells. Development 144:4137-4147|
|Rahmoun, Massilva; Lavery, Rowena; Laurent-Chaballier, Sabine et al. (2017) In mammalian foetal testes, SOX9 regulates expression of its target genes by binding to genomic regions with conserved signatures. Nucleic Acids Res 45:7191-7211|
|Minkina, Anna; Lindeman, Robin E; Gearhart, Micah D et al. (2017) Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary. Dev Biol 424:208-220|
|Zhang, Teng; Oatley, Jon; Bardwell, Vivian J et al. (2016) DMRT1 Is Required for Mouse Spermatogonial Stem Cell Maintenance and Replenishment. PLoS Genet 12:e1006293|
|Murphy, Mark W; Lee, John K; Rojo, Sandra et al. (2015) An ancient protein-DNA interaction underlying metazoan sex determination. Nat Struct Mol Biol 22:442-51|
|Lindeman, Robin E; Gearhart, Micah D; Minkina, Anna et al. (2015) Sexual cell-fate reprogramming in the ovary by DMRT1. Curr Biol 25:764-71|
|Lambeth, Luke S; Raymond, Christopher S; Roeszler, Kelly N et al. (2014) Over-expression of DMRT1 induces the male pathway in embryonic chicken gonads. Dev Biol 389:160-72|
|Zhang, Teng; Murphy, Mark W; Gearhart, Micah D et al. (2014) The mammalian Doublesex homolog DMRT6 coordinates the transition between mitotic and meiotic developmental programs during spermatogenesis. Development 141:3662-71|
|Minkina, Anna; Matson, Clinton K; Lindeman, Robin E et al. (2014) DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Dev Cell 29:511-520|
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