We identified the first widely conserved class of sexual regulatory genes, transcription factors related to the Drosophila doublesex gene. These share a unique zinc finger DNA binding domain we named the DM domain. In the current funding cycle we have investigated the function of Dmrt1, a mammalian member of this gene family. Human DMRT1 maps to a short segment on chromosome 9p that is deleted in testis dysgenesis. We showed that a null mutation in murine Dmrt1 causes severe defects in testis differentiation and causes sex reversal on at least one strain background. Our expression studies in other species showed that Dmrt1 is probably required for testis development in all vertebrates, including those with highly diverged sex determination mechanisms. The objective of the work we propose is to elucidate the mechanisms by which Dmrt1 and two related genes control mammalian gonad development, at both the genetic and molecular levels. We have four aims.
In Aim 1, we investigate which of the known sexual regulatory genes Dmrt1 controls in the embryonic gonad. We also will test the function of a related gene, Dmrt3. Dmrt3 is expressed in the embryonic testis and its human homologue, like DMRT1, is affected by sex reversing human 9p deletions.
In Aim 2 we search for additional targets of Dmrt1 regulation in the testis, and test which are regulated directly.
In Aim 3 we investigate how the Dmrt1 protein controls transcription, testing the functional importance of candidate transcriptional coregulators that specifically interact with Dmrt1.
In Aim 4, we investigate the role in gonad development of Dmrt5, an ovary-specific gene related to Dmrt1, testing whether it plays a role in females analogous to that of Dmrt1 in males. Our work will help to reveal the molecular basis of mammalian sexual differentiation and to establish a pathway of regulatory genes. This will also advance our understanding of the etiology of human congenital defects in this critical process.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059152-08
Application #
7056779
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Haynes, Susan R
Project Start
1999-05-01
Project End
2007-09-16
Budget Start
2006-05-01
Budget End
2007-09-16
Support Year
8
Fiscal Year
2006
Total Cost
$397,868
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
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
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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