Sexual dimorphism is a fundamental feature of development in virtually all animals, and affects many tissues and cell types in the body. In the nematode Caenorhabditis elegans, the activity of a single gene, tra-1, is necessary and sufficient to dictate whether the entire body develops as male or female. If tra-1 is active, all tissues differentiate as female, whereas if tra-1 is inactive, all tissues differentiate as male. Thus tra-1 is an ideal candidate with which to study sexual differentiation. In addition, C. elegans is an ideal organism in which to perform such studies because the two sexes differ extensively, development can be analyzed at the single cell level, and powerful molecular and genetic tools exist. In this project I want to answer two basic questions: first, how does mab-3, a gene regulated by tra-1, regulate male sexual development and behavior, and second, what genes does tra-1 control in the gonad and in sex-specific muscles. How does the activity of tra-1 direct sexual differentiation? To find out, I propose to study genes that are regulated by tra-1, using two approaches. The first is to examine mab-3, a tra-1 target gene we identified previously that controls male development of sense organs and also is required for male behavior. mab-3 is related to sexual regulators in insects and vertebrates, suggesting that sexual development occurs by similar mechanisms in distantly related animals. DMRT1, a gene related to mab-3, is implicated in human testis development and sex reversal syndromes. We will use genetic screens to identify genes regulated by mab-3 that are important for sense organ development. We also will study which sensory neurons require mab-3 for male behavior. The second approach is to identify new genes that are controlled by tra-1. To find these genes we will use DNA microarrays, which allow us to rapidly identify sex- specific mRNAs from the two sexes. We will use RNA interference (RNAi) to test the functions of sex-specific genes and will study the expression of those of interest. From this screen, we will select a small number of genes for further study, concentrating on those that appear to be directly regulated by tra-1 and act early in development to specific sex-specific differentiation of the gonad and musculature. These experiments will ultimately reveal in molecular detail how tra-1 controls sexual differentiation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Carter, Anthony D
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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
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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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