Human Molecular Genetics Advance Access published online on July 9, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn193
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Stabilization of β-catenin in XY gonads causes male-to-female sex-reversal
1 Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710 3 Departments of Internal Medicine and Pharmacology, University of Texas Southwestern, Dallas, Texas 75390 4 Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo, Kyoto 606-8501, Japan
* To whom correspondence should be addressed. Blanche Capel. Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710. Phone (919) 684-6390. Fax (919) 668-3467. E-mail: b.capel{at}cellbio.duke.edu
Received February 27, 2008; Revised July 3, 2008; Accepted July 3, 2008
During mammalian sex determination, expression of the Y-linked gene Sry shifts the bipotential gonad towards a testicular fate by upregulating a feed forward loop between FGF9 and SOX9 to establish SOX9 expression in somatic cells. We previously proposed that these signals are mutually antagonistic with counteracting signals in XX gonads, and that a shift in the balance of these factors leads to either male or female development. Evidence in mice and humans suggests that the male pathway is opposed by the expression of two signals, WNT4 and R-SPONDIN-1 (RSPO1), that promote the ovarian fate and block testis development. Both of these ligands can activate the canonical Wnt signaling pathway. Duplication of the distal portion of chromosome 1p, which includes both WNT4 and RSPO1, overrides the male program and causes male-to-female sex reversal in XY patients. To determine if activation of β-catenin is sufficient to block the testis pathway we have ectopically expressed a stabilized form of β-catenin in the somatic cells of XY gonads. Our results show that activation of β-catenin in otherwise normal XY mice effectively disrupts the male program and results in male-to-female sex-reversal. The identification of β-catenin as a key pro-ovarian and anti-testis signaling molecule will further our understanding of the mechanisms controlling sex determination and the molecular mechanisms that lead to sex-reversal.
2 Current Address: Cato Research, Ltd, Durham, North Carolina 27713
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