Sexual differentiation is central to normal development and human disease but the molecular mechanisms controlling it remain poorly understood. The long-term goal of this project is to use C. elegans to understand the molecular basis of sexual dimorphism and sex-specific organogenesis. The overall strategy of the PI is to use C. elegans to define conserved factors regulating sexual dimorphism and reveal mechanisms that control sex-specific development, and then examine how homologous factors control sexual dimorphism in mice. This unique approach has yielded major advances such as the discovery of the vertebrate Dmrt1 genes, which are involved in sex determination, gonadal differentiation, DSD, and testicular cancer. The main foci of this application are how the master sex-determining gene TRA-1 imposes sex-specific development and controls oogenesis in C. elegans, and how gonad-specific regulators control early gonadogenesis. Guided by strong preliminary data, the specific aims are 1) to determine how TRA-1 controls sexual differentiation and oogenesis by identifying the genes regulated by TRA-1 and dissecting their functions in reproductive tissues;and 2) to determine how organ-specific regulators control gonad sexual dimorphism by combining isolated cell transcriptome analysis with functional studies. The proposed research will uncover the molecular basis of a critical but poorly understood aspect of development, using innovative approaches and technologies including genome-wide ChIP analysis (ChIP-seq) and cell type-specific transcriptome analysis. This work has direct relevance to human health: TRA-1 is the nematode homolog of the GLI oncoprotein, which is involved in human cancer and birth defects. Furthermore, failure of sexual differentiation or gonadal differentiation causes human sex reversal, sexual ambiguity, urogenital malformation, infertility, and gonadal cancer, which are common and serious medical conditions but usually of unknown etiology. Work funded by this grant led to the discovery of vertebrate DM domain genes, which are involved in all of these human conditions. The studies in this proposal will continue to advance the mechanistic understanding of how conserved regulators impose sex specificity on organogenesis in C. elegans and will instruct ongoing studies in mammals.

Public Health Relevance

Defects in sexual differentiation are among the most common causes of human birth defects and are closely linked to human cancer. The genes we study in C. elegans that control sexual differentiation have human counterparts known to be involved in birth defects and cancer and we have previously used C. elegans to discover human genes involved in sexual differentiation and cancer. The detailed mechanistic studies we can perform in C. elegans therefore provide new insights into normal human development and human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Haynes, Susan R
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University of Minnesota Twin Cities
Schools of Medicine
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Weinberg, Peter; Berkseth, Matthew; Zarkower, David et al. (2018) Sexually Dimorphic unc-6/Netrin Expression Controls Sex-Specific Maintenance of Synaptic Connectivity. Curr Biol 28:623-629.e3
Zhang, Teng; Zarkower, David (2017) DMRT proteins and coordination of mammalian spermatogenesis. Stem Cell Res 24:195-202
Kroetz, Mary B; Zarkower, David (2015) Cell-Specific mRNA Profiling of the Caenorhabditis elegans Somatic Gonadal Precursor Cells Identifies Suites of Sex-Biased and Gonad-Enriched Transcripts. G3 (Bethesda) 5:2831-41
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
Berkseth, Matt; Ikegami, Kohta; Arur, Swathi et al. (2013) TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination. Proc Natl Acad Sci U S A 110:16033-8
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
Matson, Clinton K; Zarkower, David (2012) Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity. Nat Rev Genet 13:163-74
Arur, Swathi; Ohmachi, Mitsue; Berkseth, Matt et al. (2011) MPK-1 ERK controls membrane organization in C. elegans oogenesis via a sex-determination module. Dev Cell 20:677-88
Kalis, Andrea K; Murphy, Mark W; Zarkower, David (2010) EGL-5/ABD-B plays an instructive role in male cell fate determination in the C. elegans somatic gonad. Dev Biol 344:827-35

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