NCBI Summary:
The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis. [provided by RefSeq, Jul 2008]
General function
Ligand
Comment
Cellular localization
Secreted
Comment
Ovarian function
Steroid metabolism
Comment
Transcriptome profiling of bovine ovarian theca cells treated with fibroblast growth factor 9. Schütz LF et al. (2018) We reported previously that fibroblast growth factor 9 (FGF9) acts as an antidifferentiation factor, stimulating proliferation of granulosa cells (GCs) and theca cells (TCs) while suppressing hormone-induced steroidogenesis of these cells. How FGF9 acts to simultaneously suppress steroidogenesis and stimulate proliferation remains to be fully elucidated. Thus, this study was undertaken to clarify the effects of FGF9 on the TC transcriptome. Ovaries were obtained from beef heifers at a local abattoir, TCs were isolated from large antral follicles, and cultured with or without 30 ng/mL of FGF9 for 24 h in the presence of LH and IGF-1. After treatment, total RNA was extracted from TC and processed for microarray using Affymetrix GeneChip Bovine Genome Arrays (n = 4/group). Transcriptome analysis comparing FGF9-treated TC with control TC using 1.3-fold cutoff, and a P < 0.05 significance level identified 355 differentially expressed transcripts, with 164 elements upregulated and 191 elements downregulated by FGF9. The ingenuity pathway analysis (IPA) was used to investigate how FGF9 treatment affects molecular pathways, biological functions, and the connection between molecules in bovine TC. The IPA software identified 346 pathways in response to FGF9 in TC involved in several biological functions and unveiled interesting relationships among genes related to cell proliferation (eg, CCND1, FZD5, and MYB), antioxidation/cytoprotection (eg, HMOX1 and NQO1), and steroidogenesis (eg, CYP11A1 and STAR). Overall, genes, pathways, and networks identified in this study painted a picture of how FGF9 may regulate folliculogenesis, providing novel candidate genes for further investigation of FGF9 functions in ovarian follicular development.//////////////////
Fibroblast growth factor 9 (FGF9) regulation of cyclin D1 and cyclin-dependent kinase-4 in ovarian granulosa and theca cells of cattle. Totty ML et al. (2016) To determine the mechanism by which fibroblast growth factor 9 (FGF9) alters granulosa (GC) and theca (TC) cell proliferation, cell cycle proteins that regulate progression through G1 phase of the cell cycle, cyclin D1 (CCND1) and cyclin-dependent kinase-4 (CDK4; CCND1's catalytic partner), were evaluated. Ovaries were obtained from a local abattoir, GC were harvested from small (1-5 mm) and large (8-22 mm) follicles, and TC were harvested from large follicles. GC and TC were plated in medium containing 10% fetal calf serum followed by various treatments in serum-free medium. Treatment with 30 ng/mL of either FGF9 or IGF1 significantly increased GC numbers and when combined, synergized to further increase GC numbers by threefold. Abundance of CCND1 and CDK4 mRNA in TC and GC were quantified via real-time PCR. Alone and in combination with IGF1, FGF9 significantly increased CCND1 mRNA expression in both GC and TC. Western blotting revealed that CCND1 protein levels were increased by FGF9 in TC after 6 h and 12 h of treatment, but CDK4 protein was not affected. A mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway inhibitor, U0126, significantly reduced FGF9-induced CCND1 mRNA expression to basal levels. For the first time we show that CCND1 mRNA expression is increased by FGF9 in bovine TC and GC, and that FGF9 likely uses the MAPK pathway to induce CCND1 mRNA production in bovine TC.//////////////////
Effects of fibroblast growth factor 9 on steroidogenesis and control of FGFR2IIIc mRNA in porcine granulosa cells. Evans JR 2014 et al.
The objectives of this study were to investigate the effects of fibroblast growth factor 9 (FGF9) on hormone-stimulated porcine granulosa cell proliferation and steroid production and to further elucidate the hormonal and developmental control of FGFR2IIIc gene expression in granulosa cells. Porcine ovaries were collected from a local slaughterhouse and granulosa cells were collected from small to medium (1 to 5 mm) follicles for 5 in vitro studies that were conducted. Cells were cultured for 48 h in 5% fetal calf serum plus 5% porcine serum and then treated with various combinations of FSH, IGF-I, FGF9, Sonic hedgehog (SHH), cortisol, PGE2, and/or wingless-type mouse mammary tumor virus integration site family member 5A (WNT5A) in serum-free medium for an additional 24 or 48 h. Medium was collected for analysis of steroid concentration via RIA, or RNA was collected for gene expression analysis of FGFR2IIIc via quantitative reverse transcription PCR. Fibroblast growth factor 9 stimulated (P < 0.05) IGF-I-induced estradiol production in the presence of FSH and testosterone. However, FGF9 had inconsistent effects on progesterone production, stimulating progesterone production in the presence of FSH and testosterone but inhibiting progesterone production in the presence of IGF-I, FSH, and testosterone. Cell numbers were increased (P < 0.05) by FGF9 in the presence of IGF-I and FSH but not in the presence of FSH and absence of IGF-I. For FGFR2IIIc mRNA studies, granulosa cells were treated with FSH, IGF-I, FGF9, SHH, cortisol, PGE2, or WNT5A. Follicle-stimulating hormone alone had no effect (P > 0.10) whereas IGF-I increased (P < 0.05) FGFR2IIIc mRNA abundance. Cortisol, PGE2, SHH, and WNT5A had no effect (P > 0.10) on FGFR2IIIc gene expression whereas FGF9 in the presence of FSH and IGF-I inhibited (P < 0.05) FGFR2IIIc gene expression. In an in vivo study, granulosa cells from large (7 to 14 mm) follicles had greater (P < 0.05) abundance of FGFR2IIIc mRNA than small (1 to 3 mm) or medium (4 to 6 mm) follicles. In conclusion, IGF-I-induced FGFR2IIIc mRNA may be a mechanism for increased responses to FGF9 in FSH plus IGF-I-treated granulosa cells. Fibroblast growth factor 9 and IGF-I may work together as amplifiers of follicular growth and granulosa cell differentiation by stimulating estradiol production and concomitantly stimulating granulosa cell growth in pigs.
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FIBROBLAST GROWTH FACTOR-9, A LOCAL REGULATOR OF OVARIAN FUNCTION. Drummond AE et al. Fibroblast growth factor 9 (FGF9) is widely expressed in embryos and fetuses and has been shown to be involved in male sex determination, testicular cord formation and Sertoli cell differentiation. Given its male gender bias, the ovary has not been reported to express FGF9 nor has a role in ovarian function been explored. We report here, that FGF9 mRNA and protein are present in the rat ovary and provide evidence that supports a role for FGF9 in ovarian progesterone production. FGF9 mRNA levels as determined by real-time PCR, were high in 4 day old rat ovaries, thereafter declining and stabilising at levels approximately 30% of day 4 levels at days 12-25. Levels of FGF9 mRNA in the ovary were significantly higher than that present in adult testis, at all ages studied. The FGF9 receptors, FGFR2 and FGFR3 mRNAs were present in post natal and immature rat ovary and appeared to be constitutively expressed. FGF9 protein was localized to theca, stromal cells and corpora lutea and FGFR2 and FGFR3 proteins to granulosa cells, theca cells, oocytes and corpora lutea, by immunohistochemistry. Follicular differentiation induced by gonadotropin treatment reduced the expression of FGF9 mRNA by immature rat ovaries, whereas the estrogen stimulated development of large preantral follicles had no significant effect. In vitro, FGF9 stimulated progesterone production by granulosa cells beyond that elicited by a maximally stimulating dose of FSH. When the granulosa cells were pretreated with FSH to induce LH receptors, FGF9 was found not to be as potent as LH in stimulating progesterone production, nor did it enhance LH stimulated production. The combined treatments of FSH/FGF9 and FSH/LH however, were most effective at stimulating progesterone production by these differentiated granulosa cells. Analyses of steroidogenic regulatory proteins indicate that StAR and SCC mRNA levels were enhanced by FGF9 providing a mechanism of action for the increased progesterone synthesis. In summary, the data are consistent with a paracrine role for FGF9 in the ovary.
Expression regulated by
FSH, Growth Factors/ cytokines
Comment
Effects of Fibroblast Growth Factor 9 (FGF9) on Steroidogenesis and Gene Expression and Control of FGF9 mRNA in Bovine Granulosa Cells. Schreiber NB et al. Gene expression of fibroblast growth factor-9 (FGF9) is decreased in granulosa cells (GC) of cystic follicles compared with normal dominant follicles in cattle. The objectives of this study were to investigate the effects of FGF9 on GC steroidogenesis, gene expression, and cell proliferation and to determine the hormonal control of GC FGF9 production. GC were collected from small (1-5 mm) and large (8-22 mm) bovine follicles and treated in vitro with various hormones in serum-free medium for 24 or 48 h. In small- and large-follicle GC, FGF9 inhibited (P < 0.05) IGF-I-, dibutyryl cAMP-, and forskolin-induced progesterone and estradiol production. In contrast, FGF9 increased (P < 0.05) GC numbers induced by IGF-I and 10% fetal calf serum. FGF9 inhibited (P < 0.05) FSHR and CYP11A1 mRNA abundance in small- and large-follicle GC but had no effect (P > 0.10) on CYP19A1 or StAR mRNA. In the presence of a 3?hydroxysteroid dehydrogenase inhibitor, trilostane, FGF9 also decreased (P < 0.05) pregnenolone production. IGF-I inhibited (P < 0.05) whereas estradiol and FSH had no effect (P > 0.10) on FGF9 mRNA abundance. TNFa and wingless-type mouse mammary tumor virus integration site family member-3A decreased (P < 0.05) whereas T(4) and sonic hedgehog increased (P < 0.05) FGF9 mRNA abundance in control and IGF-I-treated GC. Thus, GC FGF9 gene expression is hormonally regulated, and FGF9 may act as an autocrine regulator of ovarian function by slowing follicular differentiation via inhibiting IGF-I action, gonadotropin receptors, the cAMP signaling cascade, and steroid synthesis while stimulating GC proliferation in cattle.
Changes in fibroblast growth factor 9 mRNA in granulosa and theca cells during ovarian follicular growth in dairy cattle. Schütz LF et al. (2016) Fibroblast growth factor 9 (FGF9) has been suggested to act as an antidifferentiation factor in cattle by reducing steroidogenesis and increasing cell proliferation in granulosa (GC) and theca (TC) cells. The objective of this study was to characterize FGF9 mRNA abundance in GC and TC during development of dominant follicles in dairy cattle. Estrous cycles of nonlactating dairy cattle were synchronized, and ovaries were collected on either d 3 to 4 (n = 8) or 5 to 6 (n = 8) postovulation for GC and TC RNA extraction from small (1-5 mm), medium (5.1-8 mm), and large (8.1-18 mm) follicles for PCR analysis. The FGF9 mRNA abundance was greater in GC than in TC. In GC, FGF9 mRNA abundance was greater in small, medium, and large estrogen-inactive i.e., concentrations of estradiol (E2) < progesterone (P4) follicles than in large E2-active (i.e., concentrations of E2 > P4) follicles at both early (d 3-4) and late (d 5-6) growing phases of first dominant follicle. Abundance of FGF9 mRNA increased in medium-sized follicles from early to late growing phase of the dominant follicle. In TC, FGF9 mRNA abundance was greater in large E2-inactive follicles than in large E2-active follicles on d 3 to 4 postovulation; no significant differences in TC FGF9 mRNA existed among follicle types on d 5 to 6 postovulation. Correlations among levels of follicular fluid hormones and FGF9 mRNA levels revealed significant negative correlations between GC FGF9 mRNA abundance and follicular fluid E2 (r = -0.68), free IGF-1 (r = -0.63), and E2-to-P4 ratio (r = -0.58). In summary, abundance of FGF9 mRNA in GC and TC increases in medium-sized follicles during development of dominant follicles and is less in dominant E2-active than subordinate E2-inactive follicles, suggesting that FGF9 signaling could contribute to normal follicle development and steroidogenesis in dairy cattle.//////////////////
Expression and effect of fibroblast growth factor 9 (FGF9) in bovine theca cells. Schreiber NB et al. FGF9 protein affects granulosa cell function but is localized mostly to theca and stroma cells of rat ovaries. The objectives of this study were to determine the: 1) effects of FGF9 on theca cell steroidogenesis, gene expression and cell proliferation, 2) mechanism of action of FGF9 on theca cells, and 3) hormonal control of FGF9 mRNA expression in theca cells. Bovine ovaries were collected from a local slaughterhouse and theca cells were collected from large (8-22 mm) follicles, and treated with various hormones in serum-free medium for 24 h or 48 h. FGF9 caused a dose-dependent inhibition (P < 0.05) of LH- and LH+IGF1-induced androstenedione and progesterone production. Also, FGF9 inhibited (P < 0.05) LH+IGF1-induced expression of LHCGR, CYP11A1 and CYP17A1 mRNA (via real-time RT-PCR) in theca cells. FGF9 had no effect (P > 0.10) on StAR mRNA abundance. Furthermore, FGF9 inhibited dbcAMP-induced progesterone and androstenedione production in LH+IGF1-treated theca cells. In contrast, FGF9 increased (P < 0.05) the number of bovine theca cells. Abundance of FGF9 mRNA in granulosa and theca cells was severalfold greater (P < 0.05) in small (1-5 mm) vs. large follicles. TNFalpha and WNT5A increased (P < 0.05) abundance of FGF9 mRNA in theca cells. In summary, expression of FGF9 mRNA in theca cells is developmentally and hormonally regulated. FGF9 may act as an autocrine regulator of ovarian function in cattle by slowing theca cell differentiation via inhibiting LH+IGF1 action via decreasing gonadotropin receptors and the cAMP signaling cascade while stimulating proliferation of theca cells.
FGF9 suppresses meiosis and promotes male germ cell fate in mice. Bowles J et al. Sex determination of mammalian germ cells occurs during fetal development and depends on signals from gonadal somatic cells. Previous studies have established that retinoic acid (RA) triggers ovarian germ cells to enter meiosis and thereby commit to oogenesis, whereas in the developing testis, the enzyme CYP26B1 degrades RA and germ cells are not induced to enter meiosis. Using in vitro and in vivo models, we demonstrate that fibroblast growth factor 9 (FGF9) produced in the fetal testis acts directly on germ cells to inhibit meiosis; in addition, FGF9 maintains expression of pluripotency-related genes and upregulates markers associated with male germ cell fate. We conclude that two independent and mutually antagonistic pathways involving RA and FGF9 act in concert to determine mammalian germ cell sexual fate commitment and support a model in which the mitosis/meiosis switch is robustly controlled by both positive and negative regulatory factors.
The human cumulus-oocyte complex gene-expression profile. Assou S et al. BACKGROUND: The understanding of the mechanisms regulating human oocyte maturation is still rudimentary. We have identified transcripts differentially expressed between immature and mature oocytes and cumulus cells. METHODS: Using oligonucleotide microarrays, genome-wide gene expression was studied in pooled immature and mature oocytes or cumulus cells from patients who underwent IVF. RESULTS: In addition to known genes, such as DAZL, BMP15 or GDF9, oocytes up-regulated 1514 genes. We show that PTTG3 and AURKC are respectively the securin and the Aurora kinase preferentially expressed during oocyte meiosis. Strikingly, oocytes overexpressed previously unreported growth factors such as TNFSF13/APRIL, FGF9, FGF14 and IL4 and transcription factors including OTX2, SOX15 and SOX30. Conversely, cumulus cells, in addition to known genes such as LHCGR or BMPR2, overexpressed cell-to-cell signalling genes including TNFSF11/RANKL, numerous complement components, semaphorins (SEMA3A, SEMA6A and SEMA6D) and CD genes such as CD200. We also identified 52 genes progressively increasing during oocyte maturation, including CDC25A and SOCS7. CONCLUSION: The identification of genes that were up- and down-regulated during oocyte maturation greatly improves our understanding of oocyte biology and will provide new markers that signal viable and competent oocytes. Furthermore, genes found expressed in cumulus cells are potential markers of granulosa cell tumours.
Follicle stages
Comment
Phenotypes
Mutations
2 mutations
Species: None
Mutation name: type: targeted overexpression fertility: subfertile Comment: The mole genome reveals regulatory rearrangements associated with adaptive intersexuality. M Real F et al. (2020) Linking genomic variation to phenotypical traits remains a major challenge in evolutionary genetics. In this study, we use phylogenomic strategies to investigate a distinctive trait among mammals: the development of masculinizing ovotestes in female moles. By combining a chromosome-scale genome assembly of the Iberian mole, Talpa occidentalis, with transcriptomic, epigenetic, and chromatin interaction datasets, we identify rearrangements altering the regulatory landscape of genes with distinct gonadal expression patterns. These include a tandem triplication involving CYP17A1, a gene controlling androgen synthesis, and an intrachromosomal inversion involving the pro-testicular growth factor gene FGF9, which is heterochronically expressed in mole ovotestes. Transgenic mice with a knock-in mole CYP17A1 enhancer or overexpressing FGF9 showed phenotypes recapitulating mole sexual features. Our results highlight how integrative genomic approaches can reveal the phenotypic impact of noncoding sequence changes.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: infertile - ovarian defect Comment: Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Colvin JS et al. (2001) Fgfs direct embryogenesis of several organs, including the lung, limb, and anterior pituitary. Here we report male-to-female sex reversal in mice lacking Fibroblast growth factor 9 (Fgf9), demonstrating a novel role for FGF signaling in testicular embryogenesis. Fgf9(-/-) mice also exhibit lung hypoplasia and die at birth. Reproductive system phenotypes range from testicular hypoplasia to complete sex reversal, with most Fgf9(-/-) XY reproductive systems appearing grossly female at birth. Fgf9 appears to act downstream of Sry to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis. While Sry is found only in some mammals, Fgfs are highly conserved. Thus, Fgfs may function in sex determination and reproductive system development in many species.//////////////////Fgf9 appeared to act downstream of Sry (480000) to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis.