Loss of &lt;i&gt;R-Spondin1&lt;/i&gt; and &lt;i&gt;Foxl2&lt;/i&gt; Amplifies Female-to-Male Sex Reversal in XX Mice

Auguste, Aurélie; Chassot, Anne-Amandine; Gregoire, Elodie P.; Renault, Ludovic; Pannetier, Maëlle; Treier, Mathias; Pailhoux, Eric; Chaboissier, Marie-Christine

doi:10.1159/000334517

Cited by 60 publications

(61 citation statements)

References 167 publications

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“…In the mouse, Foxl2 is the earliest known ovarian marker, its expression being detectable from 12.0 d.p.c. (Auguste et al 2011). Nevertheless, Foxl2 K/K mice develop normally until birth, and no perinatal sex reversal is observed (Schmidt et al 2004, Uda et al 2004.…”

Section: Sex Determination and Early Ovarian Developmentmentioning

confidence: 99%

FOXL2: a central transcription factor of the ovary

Georges¹,

Auguste²,

Bessière³

et al. 2013

Journal of Molecular Endocrinology

138

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Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes.

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Section: Sex Determination and Early Ovarian Developmentmentioning

confidence: 99%

FOXL2: a central transcription factor of the ovary

Georges¹,

Auguste²,

Bessière³

et al. 2013

Journal of Molecular Endocrinology

138

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“…In the embryonic mouse ovary, Foxl2 expression is partly dependent on RSPO1 and CTNNB1 (Manuylov et al 2008, Auguste et al 2011, whereas it is normally expressed in the Wnt4 K/K ovary (Manuylov et al 2008), suggesting that Foxl2 is expressed in two different somatic cell populations. Moreover, simultaneous deletion of Foxl2 K/K and Wnt4 K/K , as well as Foxl2…”

Section: Rspo1 Wnt4 and Foxl2 Relationship In Ovarian Developmentmentioning

confidence: 99%

“…and Rspo1 K/K , promotes early female-to-male sex reversal (Ottolenghi et al 2007, Auguste et al 2011, indicating that Foxl2 and Rspo1/Wnt4 have Figure 2 Role of Rspo1 and Wnt4 during sexual differentiation. During embryonic development of WT ovaries (top), Rspo1 expression by somatic cells at 12.5 dpc first induces the proliferation, then differentiation of female germ cells into oogonia at 12.5 and 14.5 dpc respectively (pink arrows).…”

Section: Rspo1 Wnt4 and Foxl2 Relationship In Ovarian Developmentmentioning

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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“…Originally, the FOXL2 gene was considered to play a role in the sex determination and generation of sex-reversal phenotype in goat (Auguste et al, 2011;Boulanger et al, 2014). In addition, previous studies have shown that a somatic missense mutation in the FOXL2 gene, which is expressed in the ovary, have a high correlation to granulosa cell tumors (Schmidt et al, 2004;Gustin et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of Toll-like receptors in goat dominant and nondominant follicles

Zhao

Chu

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The mechanism of dominant follicle selection is unclear because of its physiological complexity. However, some studies have reported that the immune system plays an important role in reproductive physiology. The objective of the current study was to investigate the differential expression of Toll-like receptors (TLRs) in the dominant (DFs) and nondominant follicles (NFs), and to determine the correlation between the expression of TLRs and the related genes, such as WNT4 and FOXL2. In this comparative study, the expression 2 G.X. E et al.Genetics and Molecular Research 15 (4): gmr15049157 levels of TLRs, WNT4, and FOXL2 genes of DFs and NFs were obtained from three Dazu black goats were estimated using the real-time PCR. Our results showed no significant difference in the expression of seven TLRs (excluding TLR2, TLR5, and TLR8), WNT4, and FOXL2 between the DFs and NFs. In addition, the mRNA expression levels of WNT4 significantly correlated with the relative expression of TLR6 (r = 0.949739, P < 0.01); however, no significant expression of the TLR genes was found to be associated with FOXL2 mRNA expression. Our results support the fact that TLRs are not involved in the process of dominant follicle selection; however, TLR6 might play a role in the development of follicles by interacting with WNT4.

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Loss of <i>R-Spondin1</i> and <i>Foxl2</i> Amplifies Female-to-Male Sex Reversal in XX Mice

Cited by 60 publications

References 167 publications

FOXL2: a central transcription factor of the ovary

FOXL2: a central transcription factor of the ovary

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

Differential expression of Toll-like receptors in goat dominant and nondominant follicles

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