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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059152-15
Application #
8581351
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Haynes, Susan R
Project Start
1999-05-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
15
Fiscal Year
2014
Total Cost
$427,387
Indirect Cost
$138,722
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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 29:511-20
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
Krentz, Anthony D; Murphy, Mark W; Zhang, Teng et al. (2013) Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line. Dev Biol 377:67-78
Chong, Tracy; Collins 3rd, James J; Brubacher, John L et al. (2013) A sex-specific transcription factor controls male identity in a simultaneous hermaphrodite. Nat Commun 4:1814
Gamble, Tony; Zarkower, David (2012) Sex determination. Curr Biol 22:R257-62
Krentz, Anthony D; Murphy, Mark W; Sarver, Aaron L et al. (2011) DMRT1 promotes oogenesis by transcriptional activation of Stra8 in the mammalian fetal ovary. Dev Biol 356:63-70
Matson, Clinton K; Murphy, Mark W; Sarver, Aaron L et al. (2011) DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476:101-4
Matson, Clinton K; Murphy, Mark W; Griswold, Michael D et al. (2010) The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Dev Cell 19:612-24
Murphy, Mark W; Sarver, Aaron L; Rice, Daren et al. (2010) Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis. Proc Natl Acad Sci U S A 107:13360-5

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