Up-Regulation of WNT-4 Signaling and Dosage-Sensitive Sex Reversal in Humans

Jordan, Brian K.; Mohammed, Mansoor; Ching, Saunders; Délot, Emmanuèle C.; Chen, Xiao Ning; Dewing, Phoebe; Swain, Amanda; Rao, P. Nagesh; Elejalde, B. Rafaël; Vilain, Éric

doi:10.1086/320125

Cited by 301 publications

(189 citation statements)

References 30 publications

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“…[21,22] Wnt4 À/À female mice are masculinized, [21] and overexpression of WNT4 might be responsible for sex reversal in a 46,XY patient carrying a duplication of 1p31-p35. [23] WNT4 and RSPO1 both induce stabilization of beta-catenin, and it is known that ectopic expression of a stable form of betacatenin in XY gonads can lead to male-to-female sex reversal. [24] The antagonism between FGF and Wnt signals during chondrocyte differentiation is well known.…”

Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 99%

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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Testis determination in most mammals is regulated by a genetic hierarchy initiated by the SRY gene. Early ovarian development has long been thought of as a default pathway switched on passively by the absence of SRY. Recent studies challenge this view and show that the ovary constantly represses male-specific genes, from embryonic stages to adulthood. Notably, the absence of the crucial ovarian transcription factor FOXL2 (alone or in combination with other factors) induces a derepression of male-specific genes during development, postnatally and, even more interestingly, during adulthood. Strikingly, in the adult, targeted ablation of Foxl2 leads to a molecular transdifferentiation of the supporting cells of the ovary, which acquire cytological and transcriptomic characteristics of the supporting cells of the testes. These studies bring many answers to the field of gonadal determination, differentiation and maintenance, but also open many questions. Keywords:.F OXL2; ovary determination; ovarian maintenance IntroductionGonadal sex determination is a process that implies a unique decision to make a testis or an ovary out of a bipotential primordium. In most mammals, sex determination is equated with testis determination, whereas ovarian determination has been considered a default process. That is, absence of the testisdetermining factor would automatically lead to the development of an ovary (in appropriate conditions). Recent articles challenge this view and show that in the ovary active mechanisms are required to maintain the differentiated state. [1,2] The bipotential gonad is made up of four presumptive cell lineages: germ cells (which have an extraembryonic origin) and three types of somatic cells. The somatic component involves the supporting cell precursors, which will give rise to Sertoli cells in the male or granulosa cells in the female, the steroidogenic precursors, which differentiate into Leydig cells (male) and theca cells (female), and finally the connective tissue cells yielding other important structures. [3] From a genetic perspective, the SRY gene is pivotal in switching on the testis-determining cascade.[4] Indeed, murine Sry transcripts appear in the presumptive Sertoli cells from 10.5 days postcoitum and for about 2 days, at the right moment for testis determination. [5] In other mammals, including man, SRY is expressed from the period of testis determination until adulthood [6]). It seems now that the main task of Sry/SRY is to directly activate the gene Sox9, which also encodes a transcription factor. Recently a gonad-specific enhancer that mediates testis Sox9 expression, called TESCO, has been identified. [7] Indeed, Sry along with the steroidogenic factor 1 (Sf1) binds to multiple elements within the TESCO. Moreover, mutation, co-transfection, and sex-reversal studies suggest the existence of a positive feedback circuit. First, Sf1 and Sry cooperatively up-regulate Sox9 transcription. Then, Sox9 and Sf1 recognize the enhancer to maintain the expression of the former in the absence of Sr...

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Section: Foxl2: a Molecular Actor In The Spotlightmentioning

confidence: 99%

FOXL2 versus SOX9: A lifelong “battle of the sexes”

Veitia

2010

BioEssays

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“…Dose deficiency in DMRT1 activity causes male-to-female sex reversal in humans (67) as does inactivation of SOX9. (68) Inactivation of WNT4 causes female-to-male sex reversal and its duplication causes male-to-female sex reversal, (69) though a similar function has not yet been demonstrated in reptiles. Further downstream, in reptiles, the aromatase gene could become temperature sensitive in its expression, though this is now thought to be unlikely in turtles based on work on the gonad/adrenal/mesonephros (GAM) complex (but not in the gonad alone), (70) or a mutation may afford temperature sensitivity in the efficacy of the aromatase protein.…”

Section: Transition Between Gsd and Tsdmentioning

confidence: 99%

The ends of a continuum: genetic and temperature‐dependent sex determination in reptiles

Sarre¹,

Georges²,

Quinn³

2004

BioEssays

278

259

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Two prevailing paradigms explain the diversity of sex‐determining modes in reptiles. Many researchers, particularly those who study reptiles, consider genetic and environmental sex‐determining mechanisms to be fundamentally different, and that one can be demonstrated experimentally to the exclusion of the other. Other researchers, principally those who take a broader taxonomic perspective, argue that no clear boundaries exist between them. Indeed, we argue that genetic and environmental sex determination in reptiles should be seen as a continuum of states represented by species whose sex is determined primarily by genotype, species where genetic and environmental mechanisms coexist and interact in lesser or greater measure to bring about sex phenotypes, and species where sex is determined primarily by environment. To do otherwise limits the scope of investigations into the transition between the two and reduces opportunities to use studies of reptiles to advance understanding of vertebrate sex determination generally. BioEssays 26:639–645, 2004. © 2004 Wiley Periodicals, Inc.

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“…Recently, we identified an XY female with ambiguous genitalia carrying a large duplication of chromosome 1p35 including the WNT4 locus (16). We hypothesized that this patient's intersex phenotype results from a gain of WNT4 function.…”

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Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/β-catenin synergy

Jordan

Shen

Olaso

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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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 3␤-hydroxysteroid dehydrogenase activity. In vitro studies showed that Wnt4 antagonizes the functional synergy observed between the major effector of the Wnt signaling pathway, ␤-catenin and steroidogenic factor 1, and chromatin immunoprecipitation showed that Wnt4 attenuates recruitment of ␤-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 ␤-catenin at or near steroidogenic factor 1 binding sites present in multiple steroidogenic genes.

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Up-Regulation of WNT-4 Signaling and Dosage-Sensitive Sex Reversal in Humans

Cited by 301 publications

References 30 publications

FOXL2 versus SOX9: A lifelong “battle of the sexes”

FOXL2 versus SOX9: A lifelong “battle of the sexes”

The ends of a continuum: genetic and temperature‐dependent sex determination in reptiles

Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/β-catenin synergy

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