The 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. We discovered the Dmrt family of conserved transcriptional regulators and have shown that several DMRT proteins are important for gonadal development in vertebrates. Loss of DMRT1 causes severe defects in testis development and, in humans, is associated with male-to- female sex reversal. Recently we found that Dmrt1 is required in the 129/Sv mouse strain to control germ cell pluripotency, preventing these cells from forming other cell types of the body rather than sperm. The main hypothesis of this proposal is that Dmrt1 plays a central role in controlling germ line stem cells, acting at different stages both in the stem cells themselves and in surrounding support cells called Sertoli cells. We have four aims.
Aim 1 asks how DMRT1 controls germ cell pluripotency in the embryo. We will identify changes in Dmrt1 mutant embryonic germ cells as they lose their normal fate commitment, determine whether Dmrt1 controls this process in the germ cells or the Sertoli cells, and identify candidate regulators of germ cell pluripotency.
Aim 2 tests the function of DMRT1 during adult spermatogenesis, focusing on adult germ line stem cells. We will use an innovative genetic strategy to determine the role of Dmrt1 in adult germ line stem cells.
Aim 3 seeks to illuminate the function of DMRT1 by identifying the genes it directly regulates in the neonatal testis.
Aim 4 tests the hypothesis that Dmrt1 acts with the adjacent Dmrt3 gene to coordinately direct embryonic testis development, assessing the phenotype of Dmrt3 and Dmrt1Dmrt3 double mutants on sensitized genetic backgrounds. This will provide a mouse model for human sex-reversing deletions that remove the two genes. The work we propose is highly relevant to human health. DMRT1 is implicated in human infertility, in testicular dysgenesis, and in testicular cancer. Our studies may permit better diagnosis and treatment of these conditions. Furthermore, because Dmrt1 plays a role in controlling germ line pluripotency, our work may aid in the use of germ line stem cells for therapeutic cloning and for restoration of fertility after chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059152-12
Application #
7914044
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Haynes, Susan R
Project Start
1999-05-01
Project End
2011-12-31
Budget Start
2010-09-01
Budget End
2011-12-31
Support Year
12
Fiscal Year
2010
Total Cost
$475,812
Indirect Cost
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; 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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