The investigator has previously identified a mammalian gene, DMRT1, likely to play a role in sex determination by virtue of its relatedness to both the male abnormal 3 (mab-3) gene of C.elegans and the doublesex (dsx) gene of Drosophila. The investigator originally cloned the mab-3 gene and showed that it plays a role in the well-defined sex development pathway of C. elegans, where it is needed for the formation of male sense organs and to prevent males from making yolk proteins. He also cloned a human relative, DMRT1, which he showed to be testis-specific in adults. The human gene maps to a region of chromosome 9 required for male development. The mouse homologue, Dmrt1, was also cloned and has been shown to be expressed in the embryonic gonad as soon as this tissue begins to form. Mab-3, dsx and DMRT1 all contain one or two DNA binding domains which chelate zinc but are distinct from zinc finger domains. The objective of the proposed work is to test the role of DMRT1/Dmrt1 in human and mouse sex determination.
The first aim will test whether sex-reversed people, XY female and XX males, have mutations in the DMRT1 gene.
The second aim i s to knock out the Dmrt1 gene in mouse and test the consequences on sexual development and on expression of other sex determining genes.
The third aim i s to investigate the DNA binding and transcriptional regulatory properties of Dmrt1 both in vitro and in cultured cells, to test whether it physically interacts with other sex determining proteins, and to ask what genes it regulates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM059152-01
Application #
2825060
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
168559177
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
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
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
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

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