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First published online August 2, 2004
doi: 10.1242/10.1242/dev.01266
1 Department of Maternal and Fetal Health, Samuel Lunenfeld Research Institute,
Mount Sinai Hospital, University of Toronto, Ontario M5G 1X5, Canada
2 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710,
USA
3 Department of Internal Medicine and Pharmacology, University of Texas
Southwestern Medical Center, Dallas, TX 75390, USA
4 Division of Nephrology, St Michael's Hospital, University of Toronto, Toronto,
Ontario M5B 1W8, Canada
Author for correspondence (e-mail:
quaggin{at}mshri.on.ca)
Accepted 7 May 2004
Congenital defects in genital and/or gonadal development occur in 1 in 1000 humans, but the molecular basis for these defects in most cases remains undefined. We show that the basic helix-loop-helix transcription factor Pod1 (capsulin/epicardin/Tcf21) is essential for normal development of the testes and ovaries, and hence for sexual differentiation. The gonads of Pod1 knockout (KO) mice were markedly hypoplastic, and the urogenital tracts of both XX and XY mice remained indistinguishable throughout embryogenesis. Within Pod1 KO gonads, the number of cells expressing the cholesterol side-chain cleavage enzyme (Scc) was increased markedly. Biochemical and genetic approaches demonstrated that Pod1 transcriptionally represses steroidogenic factor 1 (Sf1/Nr5a1/Ad4BP), an orphan nuclear receptor that regulates the expression of multiple genes (including Scc) that mediate sexual differentiation. Our results establish that Pod1 is essential for gonadal development, and place it in a transcriptional network that orchestrates cell fate decisions in gonadal progenitors.
Key words: Pod1, Tcf21, Sf1, Gonadogenesis, Testis development, Sex reversal, Leydig cell
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