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
Tahara, Naoyuki; Kawakami, Hiroko; Zhang, Teng et al. (2018) Temporal changes of Sall4 lineage contribution in developing embryos and the contribution of Sall4-lineages to postnatal germ cells in mice. Sci Rep 8:16410
Desmaris, Elodie; Keruzore, Marc; Saulnier, Amandine et al. (2018) DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors. J Neurosci 38:9105-9121
De Clercq, Sarah; Keruzore, Marc; Desmaris, Elodie et al. (2018) DMRT5 Together with DMRT3 Directly Controls Hippocampus Development and Neocortical Area Map Formation. Cereb Cortex 28:493-509
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
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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 25:764-771

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