FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription

Blount, Amy L.; Schmidt, Karsten; Justice, Nicholas J.; Vale, Wylie; Fischer, Wolfgang; Bilezikjian, Louise M.

doi:10.1074/jbc.m806676200

Cited by 101 publications

(127 citation statements)

References 69 publications

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“…Accordingly, the knock-out of Foxl2, constitutively or only in gonadotrope cells, leads to a defect in FSH production (Justice et al 2011, Tran et al 2013. Interestingly, cooperation of FOXL2 with SMAD3 is also observed on the promoter of the Fst gene in the pituitary and GCs (Blount et al 2009. Thus, SMAD3 seems to be a key partner of FOXL2 in several contexts.…”

Section: Putative Roles Of Foxl2 During Folliculogenesismentioning

confidence: 93%

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: Putative Roles Of Foxl2 During Folliculogenesismentioning

confidence: 93%

FOXL2: a central transcription factor of the ovary

Georges¹,

Auguste²,

Bessière³

et al. 2013

Journal of Molecular Endocrinology

138

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“…6), it is possible that FOXL2 and SF-1 compete for this site, leading to loss of transcriptional regulation. In addition to SF-1, FOXL2 transcriptional regulation may be altered by other transcription factors known to bind to FOXL2 , Blount et al 2009, Kim et al 2009, Lamba et al 2009), as well as FOXL2 binding to itself (Lamba et al 2009, Benayoun et al 2010, Fleming et al 2010. Further, posttranslational modifications such as sumoylation (Marongiu et al 2010, phosphorylation (Benayoun et al 2008a, and acetylation (Benayoun et al 2008a) may all act to modify FOXL2 transcriptional activity under the influence of FSH and the various signaling cascades that have been identified in granulosa cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Mouse forkhead L2 maintains repression of FSH-dependent genes in the granulosa cell

Kuo¹,

Fan²,

Bentsi-Barnes³

et al. 2012

Reproduction

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The forkhead transcription factor forkhead box L2 (FOXL2) is expressed in granulosa cells of small and medium follicles in the mouse ovary. Foxl2 female knockout mice exhibit primordial follicle depletion and primary ovarian failure, but evidence from adult female conditional Foxl2 knockout mice suggests that FOXL2 may also play a significant role in maintenance of ovarian differentiation at stages beyond the primordial follicle and initial wave of folliculogenesis. We previously showed that human FOXL2 functions as a transcriptional repressor of several key genes involved in granulosa cell proliferation and differentiation, including steroidogenic acute regulatory protein (STAR), P450aromatase (CYP19A1 (CYP19)), P450scc (CYP11A1 (CYP11A)), and cyclin D2 (CCND2). To elucidate the role of mouse FOXL2, we determined its role in transcriptional regulation in Chinese hamster ovary (CHO) cells and then confirmed our findings in mouse granulosa cells. We found that mouse FOXL2 represses the activities of the mouse Star, Cyp19a1, Cyp11a1 promoters in CHO cells, but may not repress the Ccnd2 promoter, and identified the minimal mouse Star, Cyp19a1, and Cyp11a1 promoter regions responsive to FOXL2 regulation. We then knocked down Foxl2 in mouse granulosa cells using siRNA, which resulted in significantly increased expression levels of mouse Star, Cyp19a1, and Cyp11a1 but not Ccnd2. To increase Foxl2 expression levels, we generated a mouse Foxl2 lentiviral construct and used it to infect mouse granulosa cells. Following lentiviral infection, the expression levels of mouse Star, Cyp19a1, and Cyp11a1, but not Ccnd2, decreased significantly. These data confirm that mouse FOXL2 functions as a transcriptional repressor of key granulosa cell genes that influence ovarian development.

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“…A role for the SMAD3-MH1 domain in FSH synthesis is only observed when SMAD4 is absent (as demonstrated here). Second, the SMAD3-MH2 domain is phosphorylated by the type I receptor (in response to ligand binding and receptor complex activation) and mediates the protein interactions with both SMAD4 and FOXL2 (32,39,40,46,47). Based on these observations, one could argue that SMAD3 may not need to directly bind the Fshb promoter to regulate its transcription under normal conditions.…”

Section: Smad3 Regulates Fsh Synthesis In Vivo-mentioning

confidence: 99%

“…In contrast, such a sequence exists in exon 4, allowing the C-terminal half of SMAD3 to be translated in frame. This includes the entirety of the MH2 domain, which is phosphorylated by activin type I receptors, and interacts with SMAD4 and FOXL2 (39,40). In vitro, this truncated protein functions identically to full-length SMAD3, in the presence of SMAD4 (36).…”

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confidence: 99%

SMAD3 Regulates Follicle-stimulating Hormone Synthesis by Pituitary Gonadotrope Cells in Vivo

Schang

Boehm

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangPituitary follicle-stimulating hormone (FSH) is an essential regulator of fertility in females and of quantitatively normal spermatogenesis in males. Pituitary-derived activins are thought to act as major stimulators of FSH synthesis by gonadotrope cells. In vitro, activins signal via SMAD3, SMAD4, and forkhead box L2 (FOXL2) to regulate transcription of the FSH␤ subunit gene (Fshb). Consistent with this model, gonadotropespecific Smad4 or Foxl2 knock-out mice have greatly reduced FSH and are subfertile. The role of SMAD3 in vivo is unresolved; however, residual FSH production in Smad4 conditional knockout mice may derive from partial compensation by SMAD3 and its ability to bind DNA in the absence of SMAD4. To test this hypothesis and determine the role of SMAD3 in FSH biosynthesis, we generated mice lacking both the SMAD3 DNA binding domain and SMAD4 specifically in gonadotropes. Conditional knock-out females were hypogonadal, acyclic, and sterile and had thread-like uteri; their ovaries lacked antral follicles and corpora lutea. Knock-out males were fertile but had reduced testis weights and epididymal sperm counts. These phenotypes were consistent with those of Fshb knock-out mice. Indeed, pituitary Fshb mRNA levels were nearly undetectable in both male and female knock-outs. In contrast, gonadotropin-releasing hormone receptor mRNA levels were significantly elevated in knock-outs in both sexes. Interestingly, luteinizing hormone production was altered in a sex-specific fashion. Overall, our analyses demonstrate that SMAD3 is required for FSH synthesis in vivo.Pituitary follicle-stimulating hormone (FSH) 2 is an essential regulator of gonadal function (1, 2). FSH acts on ovarian granulosa cells to regulate follicle development and on testicular Sertoli cells to regulate spermatogenesis (1, 3, 4). In both humans and rodents, mutations in genes regulating FSH synthesis or action cause primary amenorrhea because of the arrest of follicle development at the pre-antral or early antral stage (5-9). In contrast, the effects of these mutations in males are species-specific. For example, FSH-deficient mice are oligospermic but fertile (1), whereas FSH-deficient men are azoospermic and infertile (10 -12).FSH is a dimeric glycoprotein composed of the chorionic gonadotropin ␣ subunit (CGA) non-covalently linked to the FSH␤ subunit (FSH␤). The former is shared with other glycoprotein hormones; the latter is specific to FSH (13-16). Synthesis of the FSH␤ subunit is rate-limiting in dimeric FSH production (17-19) and is regulated by several endocrine and autocrine/paracrine factors in the hypothalamic-pituitary-gonadal axis (20,21). Among these factors, the pituitary-derived activins have been the most thoroughly investigated, both in vitro and in vivo. In recent years, particular focus has been placed on the mechanisms through which activins regulate transcription of the FSH␤ subunit gene (Fshb) (16,(22)(23)(24)(25)(26)(27).As members of the TGF␤ superfamily, activins signal through complexes of s...

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FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription

Cited by 101 publications

References 69 publications

FOXL2: a central transcription factor of the ovary

FOXL2: a central transcription factor of the ovary

Mouse forkhead L2 maintains repression of FSH-dependent genes in the granulosa cell

SMAD3 Regulates Follicle-stimulating Hormone Synthesis by Pituitary Gonadotrope Cells in Vivo

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