Jordan, B. K., Shen, J. H., Olaso, R., Ingraham, H. A. & Vilain, E. Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/-catenin synergy. Proc. Natl Acad. Sci. USA 100, 10866-10871

Department of Pediatrics, University of California, Los Angeles, Los Ángeles, California, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2003; 100(19):10866-71. DOI: 10.1073/pnas.1834480100
Source: PubMed


Genetic studies in mice suggest that Wnt4 signaling antagonizes expression of male hormones and effectively blocks male development in the female embryo. We recently identified an XY intersex patient carrying a chromosomal duplication of the WNT4 locus and proposed that this patient's feminization arises from an increased dosage of WNT4. To test this hypothesis, a transgenic mouse was generated with a large genomic P1 containing the human WNT4. Although a complete male to female intersex phenotype was not observed in WNT4 transgenic male mice, a dramatic reduction in steroidogenic acute regulatory protein was detected consistent with the marked reduction in serum and testicular androgen levels. Furthermore, a mild reduction of germ cells and a disorganized vascular system were observed in testes of WNT4 transgenic males. Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3beta-hydroxysteroid dehydrogenase activity. In vitro studies showed that Wnt4 antagonizes the functional synergy observed between the major effector of the Wnt signaling pathway, beta-catenin and steroidogenic factor 1, and chromatin immunoprecipitation showed that Wnt4 attenuates recruitment of beta-catenin to the steroidogenic acute regulatory protein promoter. Our findings suggest a model in which Wnt4 acts as an anti-male factor by disrupting recruitment of beta-catenin at or near steroidogenic factor 1 binding sites present in multiple steroidogenic genes.

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    • "Failure in the formation of coelomic vessel and germ cell, degeneration of the female reproductive tract, partial XX sex reversal (LOF) Jordan et al. (2003) and Yao et al. (2004) "
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    ABSTRACT: Sex determination refers to the developmental decision that the bipotential genital ridge to develop as a testis or an ovary. Genetic studies in mice and humans have led to crucial advances in understanding the molecular fundaments of sex determination and the mutually antagonistic signaling pathway. In this review, we summarize the current molecular mechanisms of sex determination by focusing on the known critical sex determining genes and their related signaling pathways in mammalian vertebrates from mice to humans. We also discuss the underlying dedicate balance between testis and ovary sex determination pathways, concentrating on the antagonisms between major sex determining genes.
    Journal of Molecular Endocrinology 06/2014; 53(1). DOI:10.1530/JME-14-0018 · 3.08 Impact Factor
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    • "In mammals, highly transforming Wnts have been associated to the canonical Wnt/β-catenin pathway, whereas non-transforming Wnts have been associated activate to the non-canonical pathway [4] [6]. It is noteworthy that this binary classification is becoming obsolete, thus although Wnt4 was originally described as a non-canonical Wnt (nontransforming Wnt), it has also been implicated in the activation or inhibition of the canonical Wnt pathway [55] [56] [57] [58] [59] [60] [61]. Wnt7a has also been implicated in both canonical and non-canonical Wnt signaling depending on the cell and tissue context [62] [63]. "

    InTech edited by Julianna Cseri, 08/2012; , ISBN: 978-953-51-0712-5
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    • "A human patient resembling this Wnt4 null mouse phenotype was shown to carry a mutation in WNT4 (Biason-Lauber et al. 2004). Ectopic over-expression of Wnt4 in mice resulted in disruption of testis-specific vasculature (the coelomic vessel still forms, but the structure and branching seem to be abnormal ) and inhibition of testosterone synthesis in XY embryos (Jordan et al. 2003). As the coelomic vessel forms in XX embryos with WNT4 over-expression, it suggests either, that WNT4 is not the only factor required to suppress male-specific vasculature or that the testes express another factor that is able to compensate for WNT4-mediated repression. "
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    ABSTRACT: Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.
    Chromosome Research 01/2012; 20(1):215-38. DOI:10.1007/s10577-012-9274-3 · 2.48 Impact Factor
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