Genetics of Ovarian Differentiation: &lt;i&gt;Rspo1&lt;/i&gt;, a Major Player

Chassot, Anne-Amandine; Gregoire, Elodie P.; Magliano, Marc; Lavery, Rowena; Chaboissier, Marie-Christine

doi:10.1159/000152038

Cited by 80 publications

(66 citation statements)

References 103 publications

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“…The ovarian part contained corpora albicans, indicating the presence of a former follicle. Consistent with this finding, adult XX Rspo1 K/K mice display sex reversal and are characterized by ovotestes in which the testicular part, evidenced by the presence of male-like seminiferous tubules with Sertoli cells and interstitial tissue, can form the main part of the mutant gonad, giving it the appearance of a hypoplastic testis (Chassot et al 2008b). Within the ovarian part, the presence of large abnormal cysts was noticed in 11-week-old mice (Chassot et al 2008a).…”

Section: R99supporting

confidence: 71%

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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Section: R99supporting

confidence: 71%

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

Chassot¹,

Gillot²,

Chaboissier³

2014

Reproduction

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“…Indeed, it has been proposed that Wnt4 can act on luminal cells (Hiremath et al 2007;Joshi et al 2010). Recent studies have demonstrated that Rspo1 and Wnt4 cooperate during early gonad proliferation in ovary differentiation (Chassot et al 2008(Chassot et al , 2012Tomizuka et al 2008). It will be interesting to understand whether such cooperation mediates the influence of hormones in these processes.…”

Section: Rspo1 As a Novel Hormone Mediatormentioning

confidence: 99%

R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal

et al. 2014

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Signals from the niche play pivotal roles in regulating adult stem cell self-renewal. Previous studies indicated that the steroid hormones can expand mammary stem cells (MaSCs) in vivo. However, the facilitating local niche factors that directly contribute to the MaSC expansion remain unclear. Here we identify R-spondin1 (Rspo1) as a novel hormonal mediator in the mammary gland. Pregnancy and hormonal treatment up-regulate Rspo1 expression. Rspo1 cooperates with another hormonal mediator, Wnt4, to promote MaSC self-renewal through Wnt/b-catenin signaling. Knockdown of Rspo1 and Wnt4 simultaneously abolishes the stem cell reconstitution ability. In culture, hormonal treatment that stimulates the expression of both Rspo1 and Wnt4 can completely substitute for exogenous Wnt proteins, potently expand MaSCs, and maintain their full development potential in transplantation. Our data unveil the intriguing concept that hormones induce a collaborative local niche environment for stem cells.

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“…-/-males are normally fertile and do not exhibit gross gonadal abnormalities (Chassot et al, 2008a).…”

Section: Rspo1mentioning

confidence: 99%

WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad

et al. 2012

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SUMMARYThe gonad arises from the thickening of the coelomic epithelium and then commits into the sex determination process. Testis differentiation is activated by the expression of the Y-linked gene Sry, which promotes cell proliferation and differentiation of Sertoli cells, the supporting cells of the testis. In absence of Sry (XX individuals), activation of WNT/CTNNB1 signalling, via the upregulation of Rspo1 and Wnt4, promotes ovarian differentiation. However, Rspo1 and Wnt4 are expressed in the early undifferentiated gonad of both sexes, and Axin2-lacZ, a reporter of canonical WNT/CTNNB1 signalling, is expressed in the coelomic region of the E11.5 gonadal primordium, suggesting a role of these factors in early gonadal development. Here, we show that simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of the cells of the coelomic epithelium, reducing the number of progenitors of Sertoli cells in XY mutant gonads. As a consequence, in XY Wnt4 -/-; Rspo1 -/-foetuses, this leads to the differentiation of a reduced number of Sertoli cells and the formation of a hypoplastic testis exhibiting few seminiferous tubules. Hence, this study identifies Rspo1 and Wnt4 as two new regulators of cell proliferation in the early gonad regardless of its sex, in addition to the specific role of these genes in ovarian differentiation. Jeays-Ward et al., 2004;Kim et al., 2006;Vainio et al., 1999). Similarly, Rspo1 is specifically upregulated in XX foetal gonads at E11.5 Parma et al., 2006). Loss of function of either Rspo1 or Wnt4 in XX gonads promotes: (1) ectopic steroidogenic precursors, endothelial cell migration and the formation of a coelomic vessel (Chassot et al., 2008b;Jeays-Ward et al., 2003); and (2) sex reversal of the supporting cell lineages with expression of the Sertoli cell markers, SOX9 or Dhh, and the development of ovotestes around birth (Chassot et al., 2008b;Tomizuka et al., 2008;Vainio et al., 1999). WNTs and R-spondins act synergistically by interaction of their respective receptors LRP5/6 and LGR4/5 (Carmon et al., 2011;de Lau et al., 2011;Glinka et al., 2011). R-spondin binding activates WNT/CTNNB1 signalling and can disrupt WNT/planar cell polarity signalling (Hao et al., 2012). How RSPO1 and WNT4 interact in the gonad remains to be elucidated; however, in absence of Rspo1 and its effector CTNNB1, Wnt4 upregulation is impaired, indicating that Rspo1 is required for Wnt4 upregulation in the ovary after 11.5 dpc (Chassot et al., 2008b;Liu et al., 2009;Manuylov et al., 2008;Tomizuka et al., 2008). WNT/CTNNB1 signalling is required for Foxl2 upregulation (Manuylov et al., 2008), which in turn promotes follicular differentiation (Ottolenghi et al., 2005;Schmidt et al., 2004) and homeostasis in the ovaries (Uhlenhaut et al., 2009). In addition to its role in ovarian development, Wnt4 is also involved in testis differentiation. Indeed, in XY gonads, loss of function of Wnt4 induces a delay in sex cord formation that is compensated at birth (Jeays-Ward et al., 2004). By contrast, Rspo1-/-males are nor...

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Genetics of Ovarian Differentiation: <i>Rspo1</i>, a Major Player

Cited by 80 publications

References 103 publications

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

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

R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal

WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad

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