Stabilization of β-catenin in XY gonads causes male-to-female sex-reversal

Maatouk, Danielle M.; DiNapoli, Leo; Alvers, Ashley L.; Parker, Keith L.; Taketo, Makoto Mark; Capel, Blanche

doi:10.1093/hmg/ddn193

Cited by 309 publications

(280 citation statements)

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“…An alternative model might consider that the amplifications abrogate SOX9 silencing by moving a hypothetical negative regulatory Testis development in the absence of SRY A Vetro et al element located upstream of RevSex (negative gonadal regulatory element (NGRE), dashed blue line in Figure 3), too far away to exert any influence on SOX9 promoter. In fact, SOX9 repression needs to be maintained on the XX background both in the developing gonad 26 and in the ovary, 27 in order to ensure the differentiation and maintenance of ovarian cell fate. NGRE would not be displaced, but rather included in duplications associated with brachydactylyanonychia but not with sex reversal (dark green in Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

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Duplications in the~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects. European Journal of Human Genetics (2015) 23, 1025-1032; doi:10.1038/ejhg.2014.237; published online 5 November 2014 INTRODUCTION 46,XX disorders of sex development (DSDs) are congenital conditions in which, in the presence of a female karyotype, the development of gonadal and anatomical sex is atypical, ranging from various degrees of ambiguous genitalia to phenotypic males with azoospermia. These conditions are poorly characterized, at least in subjects whose DNA does not contain SRY, the gene triggering testis differentiation in mammals. 1 In fact, in most XX males, SRY is transposed to the tip of Xp as a consequence of a recurrent Xp;Yp translocation, arising predominantly by nonallelic homologous recombination between PRKX and PRKY on a particular Y haplotypic background. 2,3 These males, usually with small testes, are essentially picked up among men with nonobstructive azoospermia.A much less well-understood category is that of the 46,XX DSDs negative for SRY. Recently, six of these cases have been reported

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Section: Discussionmentioning

confidence: 99%

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

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“…The cellular context is essential for the choice of the pathway to be activated as exemplified by WNT4. While WNT4 is able to activate canonical WNT signaling in gonadal development (Maatouk et al 2008, Liu et al 2010), it appears to induce CTNNB1-independent pathways in the kidney (Burn et al 2011). In addition to its role in canonical WNT signaling, CTNNB1 is also an important component of adherent junctions, which regulates patterning and morphogenesis.…”

Section: Wnt4 a Wingless Family Gene Involved In Many Biological Promentioning

confidence: 99%

“…In 2006, Prof. Giovanna Camerino et al identified R-spondin1 (RSPO1), a WNT signaling pathway activator, as a novel key factor involved in sexual and ovarian differentiation (Parma et al 2006). After 2 years, Prof. Blanche Capel et al showed that genetic induction of WNT/b-catenin signaling can modify the fate of the gonad by promoting the ovarian development from a gonad programed to become a testis (Maatouk et al 2008). This complemented their previous work on Wnt4, another player in the WNT signaling pathway, which showed that sex determination is governed by a balance between two antagonistic pathways (Kim et al 2006) and firmly established WNT/b-catenin signaling as a key pathway involved in female differentiation.…”

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confidence: 99%

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

Chassot¹,

Gillot²,

Chaboissier³

2014

Reproduction

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Sex differentiation is a unique developmental process. Starting from a bipotential gonad, it gives rise to the ovary and the testis, two highly specialized organs that differ morphologically and physiologically despite sharing common reproductive and endocrine functions. This highlights the specific plasticity of the gonadal precursors and the existence of complex antagonistic genetic regulation. Mammalian sex determination is controlled by paternal transmission of the Y-linked gene, sex-determining region Y (SRY). Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9; either one of these two genes is necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY/Sry and/or SOX9/Sox9 expression result in male-to-female sex reversal of XY individuals. Molecular mechanisms governing ovarian differentiation remained unknown for a long time, until the discovery of the roles of R-spondin1 (RSPO1) and WNT4. In XX individuals, activation of the b-catenin signaling pathway by the secreted proteins RSPO1 and WNT4 is required to allow granulosa cell differentiation and, in turn, ovarian differentiation. Thus, mutations in RSPO1 result in female-to-male sex reversal of XX patients, and mouse models have allowed the identification of genetic cascades activated by RSPO1 and WNT4 to regulate ovarian development. In this review, we will discuss the respective roles of RSPO1, WNT4, and the b-catenin signaling pathway during ovarian differentiation in mice.Reproduction (2014) 148 R97-R110

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“…[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. Indeed, Fgf promotes Sox9 expression and Wnt signaling leads to its degradation ( [25] and references therein).…”

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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Stabilization of β-catenin in XY gonads causes male-to-female sex-reversal

Cited by 309 publications

References 28 publications

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

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

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