Follicle‐stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2

Fortin, Jérôme; Boehm, Ulrich; Deng, Chu‐Xia; Treier, Mathias; Bernard, Daniel J.

doi:10.1096/fj.14-249532

Cited by 71 publications

(50 citation statements)

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“…Consistent with the in vitro model, conditional deletion of either Smad4 or Foxl2 from pituitary gonadotrope cells (hereafter, Smad4 cKO and Foxl2 cKO, respectively) produces profound FSH deficiency in mice in vivo (34,35). Female cKOs are subfertile, producing smaller litters (both models) at reduced frequency (Foxl2 cKO) compared with wild-type littermates (34,35).…”

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confidence: 73%

“…This contrasts with the more extreme phenotype of Fshb knock-out females, which are infertile (1). However, it is important to note that in both Smad4 and Foxl2 cKOs, females still produce some FSH, which may be sufficient to drive some ovarian follicle development (34,35). This residual FSH production may reflect the fact that there are cis-elements in the Fshb promoter where FOXL2 and SMAD4 can act independently of one another (see above and Fig.…”

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confidence: 96%

“…Female cKOs are subfertile, producing smaller litters (both models) at reduced frequency (Foxl2 cKO) compared with wild-type littermates (34,35). This contrasts with the more extreme phenotype of Fshb knock-out females, which are infertile (1).…”

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confidence: 99%

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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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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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“…Bone morphogenetic proteins play significant roles in follicular development (Juengel et al, 2004;Hussein et al, 2005) and a variety of physiological processes such as embryonic development, tissue homeostasis, apoptosis, proliferation, migration, differentiation, and bone formation (Urist, 1965;Wu and Hill, 2009;Wagner et al, 2010). More specifically to pituitary gland function, BMP receptors SMAD4 and SMAD3 were related to signaling for FSH transcription (Rejon et al, 2013;Fortin et al, 2014). Therefore, TGFβ superfamily genes could be involved in regulation of FSH secretion in pubertal Brahman heifers.…”

Section: Pituitary Gland Genes: Differentially Expressed and Interactingmentioning

confidence: 99%

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

Nguyen¹,

Reverter²,

Cánovas³

et al. 2017

Journal of Animal Science

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ABSTRACT:To understand genes, pathways, and networks related to puberty, we characterized the transcriptome of two tissues: the pituitary gland and ovaries. Samples were harvested from pre-and postpubertal Brahman heifers (same age group). Brahman heifers (Bos indicus) are older at puberty compared with Bos taurus, a productivity issue. With RNA sequencing, we identified differentially expressed (DEx) genes and important transcription factors (TF) and predicted coexpression networks. The number of DEx genes detected in the pituitary gland was 284 (P < 0.05), and VWC2L was the most DEx gene (fold change = 4.12, P = 0.01). The gene VWC2L promotes bone mineralization through transforming growth factor-β (TGFβ) signaling. Further studies of the link between bone mineralization and puberty could target VWC2L. In ovaries, 3,871 genes were DEx (P < 0.05). Four highly DEx genes were noteworthy for their function: SLC6A13 (a γ-aminobutyric acid [GABA] transporter), OXT (oxytocin), and NPY (neuropeptide Y) and its receptor NPY2R. These genes had higher ovarian expression in postpubertal heifers. The GABA and its receptors and transporters were expressed in the ovaries of many mammals, suggesting a role for this pathway beyond the brain. The OXT pathway has been known to influence the timing of puberty in rats, via modulation of GnRH. The effects of NPY at the hypothalamus, pituitary gland, and ovaries have been documented. Neuropeptide Y and its receptors are known factors in the release of GnRH, similar to OXT and GABA, although their roles in ovarian tissue are less clear. Pathways previously related to puberty such as TGFβ signaling (P = 6.71 × 10 −5 ), Wnt signaling (P = 4.1 × 10 −2 ), and peroxisome proliferator-activated receptor (PPAR) signaling (P = 4.84 × 10 −2 ) were enriched in our data set. Seven genes were identified as key TF in both tissues: HIC2, ZIC4, ZNF219, ZSCAN26, LHX1, OLIG1, and a novel gene. An ovarian subnetwork created with TF and significant ovarian DEx genes revealed five zinc fingers as regulators: ZNF507, ZNF12, ZNF512, ZNF184, and ZNF432. Recent work of hypothalamic gene expression also pointed to zinc fingers as TF for bovine puberty. Although some zinc fingers may be ubiquitously expressed, the identification of DEx genes in common across tissues points to key regulators of puberty. The hypothalamus and pituitary gland had eight DEx genes in common. The hypothalamus and ovaries had 89 DEx genes in common. The pituitary gland and ovaries had 48 DEx genes in common. Our study confirmed the complexity of puberty and suggested further investigation on genes that code zinc fingers.

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“…GnRH activates the GnRH receptor in gonadotropes, a seven membrane-spanning G-protein-coupled receptor, to maintain the basal expression of gonadotropin subunit gene transcription (12). Activins, members of transforming growth factor-␤ superfamily, regulate Fshb transcription via SMAD-and FOXL2-dependent pathways (13). Another member of the same family, follistatin, is a locally produced factor that negatively regulates Fshb transcription by preventing activin action on gonadotropes (14).…”

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Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

Wang

Graham

Hastings

et al. 2015

Journal of Biological Chemistry

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Background: DICER mediates microRNA production, and its functional role in gonadotropes is not known. Results: Deletion of Dicer in gonadotropes leads to suppression of gonadotropin synthesis and secretion and results in fertility defects. Conclusion: DICER-dependent microRNAs are critical for gonadotropin homeostasis and fertility. Significance: Understanding how microRNAs regulate gonadotropin homeostasis provides a new approach to enhance or block fertility in mammals.

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Follicle‐stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2

Cited by 71 publications

References 69 publications

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

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

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

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