Mechanisms of fibroblast growth factor signaling in the ovarian follicle. Price C et al. (2015) Fibroblast growth factors have been shown to alter growth and differentiation of reproductive tissues in a variety of species. Within the female reproductive tract, the effects of FGFs have been focused on the ovary, and the most well-studied is FGF2, which stimulates granulosa cell proliferation and decreases differentiation (decreased steroidogenesis). Other FGFs have also been implicated in ovarian function, and this review summarizes the effects of members of two subfamilies on ovarian function; the FGF7 subfamily that also contains FGF10, and the FGF8 subfamily that also contains FGF18. There are data to suggest that FGF8 and FGF18 have distinct actions on granulosa cells, despite their apparent similar receptor binding properties. Studies of non-reproductive developmental biology also indicate that FGF8 is distinct from FGF18, and that FGF7 is also distinct from FGF10 despite similar receptor binding properties. In this review, the potential mechanisms of differential action of FGF7/FGF10 and FGF8/FGF18 during organogenesis will be reviewed and placed in the context of follicle development. A model is proposed in which FGF8 and FGF18 differentially activate receptors depending on the properties of the extracellular matrix in the follicle.//////////////////
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 exhibits mitogenic activity for keratinizing epidermal cells, but essentially no activity for fibroblasts, which is similar to the biological activity of FGF7. Studies of the mouse homolog of suggested that this gene is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of lim bud formation. This gene is also implicated to be a primary factor in the process of wound healing. [provided by RefSeq, Jul 2008]
General function
Ligand, Growth factor
Comment
Cellular localization
Secreted
Comment
Ovarian function
Primary follicle growth, Preantral follicle growth, Cumulus expansion, Steroid metabolism, Oocyte maturation, Early embryo development
Comment
Fibroblast growth factor 10 markedly improves in vitro maturation of porcine cumulus-oocyte complexes. Son YJ et al. (2016) Growth factors synthesized by ovarian somatic cells affect cumulus cell expansion and oocyte maturation in vitro. Fibroblast growth factor 10 (FGF10), for example, is a known regulator of mammalian cumulus-oocyte complex maturation. In this study, we investigated the effects of 0, 5, 10, 50, and 100 ng/mL FGF10 (5F, 10F, 50F, and 100F, respectively) on in vitro cumulus cell expansion, oocyte maturation, and embryo development. The percentage of fully expanded cumulus cells at the oocyte's metaphase-II (MII) stage was significantly higher in the 10F-treated group than in the control. Transcript abundance of the cumulus cell expansion-related gene encoding hyaluronian synthase 2 (SHAS2) in cumulus cells at oocyte germinal vesicle breakdown (GVBD) was significantly higher in the 10F- and 50F-treated groups compared to untreated controls, whereas the mRNA abundance of the protease cathepsin B (CTSB) at the oocyte MII stage was remarkably decreased in the 10F-treated group. The percentage of oocytes with normal spindles was greater in the 10F- and 50F-treated group at GVBD than in the other groups; the 5F-, 10F-, and 100F-treated groups were higher than the control; and the 50F-treated group was highest at MII. The abundance of GDF9 and BMP15 transcript at GVBD and BMP15 and CCNB1 transcripts at MII increased in the 10F-treated group. Cleavage rate, blastocyst formation rate, and total cell number were significantly higher in the 5F- to 50F-treated groups. These results demonstrate that FGF10 markedly improves cumulus cell expansion, oocyte maturation, and subsequent embryo development. This article is protected by copyright. All rights reserved.//////////////////
Evidence that fibroblast growth factor 10 plays a role in follicle selection in cattle. Castilho AC et al. (2015) There is evidence that regulation of follicle selection in cattle involves locally produced growth factors. In the present study, we investigated the expression of members of the fibroblast growth factor (FGF) 7 family during follicle deviation. The largest and second largest follicles were recovered during the second day of a synchronised follicle wave and the future dominant and future subordinate follicles were identified based on diameter and cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) mRNA levels in granulosa cells. Theca cells of the future dominant follicle contained less mRNA encoding FGF7 and FGF10 compared with those from the future subordinate follicle 2.5 days after ovulation, before a significant difference between the diameters of the future dominant and future subordinate follicles could be observed, but FGF22 mRNA levels did not change. Levels of mRNA encoding FGF receptors FGFR1B and FGFR2B in theca and granulosa cells, respectively, were lower in the future dominant follicle compared with the future subordinate follicle. Addition of FGF10 to granulosa cells in vitro significantly decreased oestradiol secretion, as well as CYP19A1, FSH receptor (FSHR) and insulin-like growth factor 1 receptor (IGF1R) mRNA abundance, whereas FGF22 had no effect. We conclude that FGF10 and FGFR2B expression is increased in the future subordinate follicle before morphological deviation, which may contribute to follicle selection.//////////////////
Effect of sequential medium with fibroblast growth factor-10 and follicle stimulating hormone on in vitro development of goat preantral follicles. Almeida AP et al. (2014) A sequential medium with fibroblast growth factor-10 (FGF-10) and follicle stimulating hormone (FSH) was evaluated on the survival, ultrastructure, activation and growth rate of caprine preantral follicles submitted to long-term culture, aiming to establish an ideal in vitro culture system. Ovarian fragments were cultured for 16 days in α-MEM(+) alone or supplemented with FGF-10 and/or FSH added sequentially on different days of culture. Ovarian fragments were cultured during the first (days 0-8) and second (days 8-16) halves of the culture period, generating 10 treatments: α-MEM(+)/α-MEM(+) (cultured control), FSH/FSH, FSH/FGF-10, FSH/FSH+FGF-10, FGF-10/FGF-10, FGF-10/FSH, FGF-10/FSH+FGF-10, FSH+FGF-10/FSH+FGF-10, FSH+FGF-10/FSH and FSH+FGF-10/FGF-10. Follicle morphology, viability and ultrastructure were analyzed. The FSH/FGF-10 treatment showed a higher (P<0.05) percentage of normal follicles compared to all other treatments. In addition, follicles from the FSH/FGF-10 treatment maintained ultrastructural integrity after the culture period. After 16 days of culture, the FSH/FGF-10 and FSH/FSH treatments showed a higher percentage of activation compared to the cultured control (α-MEM(+)/α-MEM(+)). Moreover, the FSH/FGF-10 treatment promoted greater follicular and oocyte diameters compared to the fresh control. In conclusion, this study showed that a sequential medium with FSH followed by FGF-10 (FSH/FGF-10 and FSH/FSH) maintains follicular viability and ultrastructure and promotes transition from the primordial to primary stage (activation) and growth in goat preantral follicles cultured in vitro.//////////////////
Bone morphogenetic protein 15 and fibroblast growth factor 10 enhance cumulus expansion, glucose uptake and expression of genes in the ovulatory cascade during in vitro maturation of bovine cumulus-oocyte complexes. Caixeta E et al. Oocyte secreted factors (OSF) regulate differentiation of cumulus cells and are of pivotal relevance for fertility. Bone morphogenetic protein 15 (BMP15) and fibroblast growth factor 10 (FGF10) are OSFs and enhance oocyte competence by unknown mechanisms. We tested the hypothesis that BMP15 and FGF10, alone or combined in the maturation medium, enhance cumulus expansion and expression of genes in the pre-ovulatory cascade, and regulate glucose metabolism favouring hyaluronic acid production in bovine cumulus-oocyte complexes (COC). BMP15 or FGF10 increased the percentage of fully expanded COCs, but the combination did not further stimulate it. BMP15 increased cumulus cell levels of mRNA encoding ADAM10, ADAM17, AREG and EREG at 12 hours of culture, and of PTGS2, PTX3 and TSG6 at 22 hours of culture. FGF10 did not alter the expression of EGF-like factors but enhanced mRNA expression of PTGS2 at 4 hours, PTX3 at 12 hours, and TSG6 at 22 hours. FGF10 and BMP15 stimulated glucose consumption by cumulus cells but did not affect lactate production or levels of mRNA encoding glycolytic enzymes PFK and LDHA. Each growth factor increased mRNA encoding GFPTs, key enzymes in the hexosamine pathway leading to hyaluronic acid production, and BMP15 also stimulated HAS2 mRNA expression. This study provides evidence that BMP15 and FGF10 stimulate expansion of in vitro matured bovine COCs by driving glucose metabolism towards hyaluronic acid production and controlling the expression of genes in the ovulatory cascade, the first acting upon ADAM10, ADAM17, AREG and EREG, and the second on downstream genes, particularly PTGS2.
Fibroblast growth factor-10 maintains the survival and promotes the growth of cultured goat preantral follicles. Chaves RN et al. The aim of the present study was to investigate the effects of fibroblast growth factor-10 (FGF-10) on the survival, activation (transition from primordial to primary follicles), and growth of goat preantral follicles cultured in vitro. Pieces of ovarian cortex were cultured for 1 and 7 d in the absence or presence of FGF-10 (0, 1, 10, 50, 100, and 200 ng/mL). Noncultured and cultured tissues were processed and analyzed by histology, transmission electron microscopy, and viability testing. Results showed that after 7 d, a greater percentage (79.9%) of morphologically normal follicles (containing an oocyte with regular shape and uniform cytoplasm, and organized layers of granulosa cells without a pyknotic nucleus) was observed when cultured with 50 ng/mL of FGF-10 when compared with other concentrations of FGF-10 (0 ng/mL, 67.3%; 1 ng/mL, 68.2%; 10 ng/mL, 63.3%; 100 ng/mL, 64.4%; 200 ng/mL, 52.7%). Ultrastructural analyses and viability testing using fluorescent markers confirmed the follicular integrity of FGF-10 (50 ng/mL)-treated fragments after 7 d of culture. After 7 d, all FGF-10 concentrations reduced the percentage of primordial follicles and increased the percentage of developing follicles. In the presence of 50 ng/mL of FGF-10, follicles increased in diameter after 7 d of culture when compared with other concentrations tested. In conclusion, this study demonstrates that FGF-10 maintains the morphological integrity of goat preantral follicles and stimulates the growth of activated follicles in culture. The culture conditions identified here contribute to the understanding of the factors involved in goat early follicular development.
Fibroblast growth factor-10 enhances bovine oocyte maturation and developmental competence in vitro. Zhang K et al. The ability of oocytes to resume meiosis, become fertilized and generate viable pregnancies is controlled during folliculogenesis by several endocrine and paracrine factors. The aim of this work was to determine if fibroblast growth factor 10 (FGF10) is an oocyte competency factor. Transcripts for each of the four FGF receptor types (FGFR) were present in cumulus and oocytes after their extraction from follicles. FGFR1 transcripts predominated in cumulus cells whereas FGFR2 was most abundant in oocytes. Exposing cumulus-oocyte complexes to FGF10 during in vitro maturation did not affect cleavage rates, but increases (P<0.05) in the percentage of embryos at the 8-16 cell stage on day 3 and at the blastocyst stage on day 7 were evident in FGF10-supplemented oocytes. The progression of oocytes through meiosis and cumulus expansion were increased (P<0.05) by FGF10. The importance of endogenous sources of FGFs was examined by adding anti-FGF10 IgG during oocyte maturation. Blocking endogenous FGF10 activity decreased (P<0.05) the percentage of oocytes developing to blastocysts and limited (P<0.05) cumulus expansion. Expression profiles of putative cumulus and oocyte competency markers were examined for their involvement in FGF10-mediated responses. FGF10 influenced the expression of CTSB and SPRY2 in cumulus cells and BMP15 in oocytes. In summary, this work provides new insight into the importance of FGFRs and locally-derived FGF10 during oocyte maturation in cattle. Its subsequent impact on in vitro embryo development implicates it as a noteworthy oocyte competency factor.
Expression and Function of Fibroblast Growth Factor 10 and Its Receptor, Fibroblast Growth Factor Receptor 2B, in Bovine Follicles. Buratini Jr J et al. Some fibroblast growth factors (FGF) affect ovarian follicle cell growth and/or differentiation. Whereas many FGFs activate several FGF receptors, FGF7 and FGF10 primarily activate only one, FGFR2B. As FGF7 is produced by bovine theca cells and acts on granulosa cells, we tested the hypothesis that FGF10 may also play a role in folliculogenesis in cattle. Reverse transcription-polymerase chain reaction demonstrated the presence of FGF10 mRNA in oocytes and theca cells of antral follicles, and in preantral follicles. FGF10 protein was detected by immunohistochemistry in oocytes of preantral and antral follicles, and in granulosa and theca cells of antral follicles. FGF10 expression in theca cells changed during follicle development; mRNA abundance decreased with increasing follicular estradiol concentration in healthy follicles, and was lowest in highly atretic follicles. Culture of granulosa cells in serum-free medium demonstrated regulation of FGF10 receptor expression by FSH. Addition of FGF10 to cultured granulosa cells decreased estradiol but did not alter cell proliferation. These data support a role for FGF10 in signaling to granulosa cells from theca cells and/or the oocyte.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Expression of fibroblast growth factor 10 and cognate receptors in the developing bovine ovary. Castilho AC 2014 et al.
In the mammalian ovary, FGF10 is expressed in oocytes and theca cells and is a candidate for paracrine signaling to the developing granulosa cells. To gain insight into the participation of FGF10 in the regulation of fetal folliculogenesis, we assessed mRNA expression patterns of FGF10 and its receptors, FGFR1B and FGFR2B, in relation to fetal follicle dynamics and localized FGF10 protein in bovine fetal ovaries at different ages. Primordial, primary, secondary, and antral follicles were first observed on Days 75, 90, 150, and 210 of gestation, respectively. The levels of GDF9 and BMP15 mRNA, markers for primordial and primary follicles, respectively, increased during fetal ovary development in a consistent manner with fetal follicle dynamics. CYP17A1 mRNA abundance increased from Day 60 to Day 75 and then from Day 120 to Day 150, coinciding with the appearance of secondary follicles. FGF10 mRNA abundance increased from Day 90, and this increase was temporally associated with increases in FGFR1B mRNA abundance and in the population of primary follicles. In contrast, FGFR2B mRNA expression was highest on Day 60 and decreased thereafter. FGF10 protein was localized to oogonia and oocytes and surrounding granulosa cells at all fetal ages. The present data suggest a role for FGF10 in the control of fetal folliculogenesis in cattle.
/////////////////////////
Fibroblast growth factor 10 in human ovaries. Oron G et al. The expression of fibroblast growth factor 10 (FGF-10) has not been studied in human ovarian cortical follicles. The aim of the present study was to investigate the expression of FGF-10 in preantral follicles from fetuses, girls and women. Ovarian samples were obtained from 14 human fetuses at 21-33 gestational weeks and from 35 girls and women aged 5-39years. The specimens were prepared for detection of the FGF-10 protein by immunohistochemistry. Reverse-transcription PCR was applied to ovarian extracts to identify FGF-10 mRNA transcripts. In fetal tissue, the FGF-10 protein was detected in oocytes in 50% of the samples and in granulosa cells in 30%. In ovarian tissue from girls and women, the FGF-10 protein was detected in oocytes and granulosa cells in all samples. FGF-10 mRNA transcripts were present in all adult and fetal samples tested. The identification of FGF-10 at both the protein and mRNA levels suggests that FGF-10 may contribute to human preantral follicle development. Very early ovarian follicles (cellular structures that contain immature eggs) are the lifetime fertility reserve in females. Researchers are seeking further understanding of the growth signals that initiate their formation in order to develop a medically safe method for restoring fertility in cancer survivors. There is some evidence that fibroblast growth factor 10 (FGF-10) might serve as one of the triggers of ovarian follicular growth. The aim of the study was to investigate the expression of FGF-10 at both the protein and gene levels in ovaries from fetuses, girls and women. The tissue was obtained during ovarian operations or legal pregnancy termination, mainly because of fetal abnormalities, and donated by women and parents of minors. Our results revealed the presence of the FGF-10 protein in very immature follicles, both in the egg and its surrounding supporting cells. Expression was stronger and more abundant in the samples from girls and women. FGF-10 gene expression was identified in all ovaries. Our findings suggest that FGF-10 probably contributes to the interplay among various growth factors involved in the initial follicular development stages in humans.
Expression of fibroblast growth factor 10 and its receptor, fibroblast growth factor receptor 2B, in the bovine corpus luteum. Castilho AC et al. There is evidence that several fibroblast growth factors (FGFs) are involved in growth and development of the corpus luteum (CL), but many FGFs have not been investigated in this tissue, including FGF10. The objective of this study was to determine if FGF10 and its receptor (FGFR2B) are expressed in the CL. Bovine CL were collected from an abattoir and classed as corpus hemorrhagica (stage I), developing (stage II), developed (stage III), and regressed (stage IV) CL. Expression of FGF10 and FGFR2B mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). Both genes were expressed in bovine CL, and FGF10 expression did not differ between stages of CL development. FGF10 protein was localized to large and small luteal cells by immunohistochemistry. FGFR2B expression was approximately threefold higher in regressed compared to developing and developed CL (P < 0.05). To determine if FGF10 and FGFR2B expression is regulated during functional luteolysis, cattle were injected with PGF2alpha and CL collected at 0, 0.5, 2, 4, 12, 24, 48, and 64 hr thereafter (n = 5 CL/time point), and mRNA abundance was measured by real-time RT-PCR. FGF10 mRNA expression did not change during functional luteolysis, whereas FGFR2B mRNA abundance decreased significantly at 2, 4, and 12 hr after PGF2alpha, and returned to pretreatment levels for the period 24-64 hr post-PGF2alpha. These data suggest a potential role for FGFR2B signaling during structural luteolysis in bovine CL. Mol. Reprod. Dev. (c) 2007 Wiley-Liss, Inc.
Follicle stages
Primary, Secondary, Antral, Corpus luteum
Comment
FGF10 inhibits dominant follicle growth and estradiol secretion in vivo in cattle. Gasperin B et al. Fibroblast growth factors (FGFs) are involved in paracrine control of follicle development. It was previously demonstrated that FGF10 decreases estradiol secretion in granulosa cell culture and that theca cell FGF10 mRNA expression is decreased in healthy follicles from abattoir ovaries. The main objectives of the present study were to evaluate FGF10 and FGFR2b mRNA expression during follicular development in vivo, to evaluate the effect of FGF10 on follicle growth using Bos taurus taurus cows as a model and to gain more insight into the mechanisms through which FGF10 inhibits steroidogenesis. Messenger RNA encoding both FGF10 and FGFR2b (main FGF10 receptor) were significantly more expressed in subordinate follicles than in dominant follicles. The intrafollicular injection of FGF10 into the largest growing follicle at 7-8mm in diameter interrupted the dominant follicle growth in a dose dependent manner (11?0.4, 8.3?1 and 5.9?0.3mm for 0, 0.1 and 1?g/mL FGF10, at 72h after treatment; P<0.05). In a third experiment, follicles were obtained 24h after FGF10 (1?g/mL) or PBS treatment through ovariectomy. In theca cells, FGF10 treatment did not affect mRNA encoding steroidogenic enzymes, LHCGR and IGFBPs, but significantly upregulated FGF10 mRNA expression. The expression of CYP19A1 mRNA in granulosa cells was downregulated by FGF10 treatment, which was accompanied by a fifty-fold decrease in estradiol production, and decreased cyclin D2 mRNA. These results shown that FGF10 and its receptor FGFR2b are more expressed in subordinate follicles and provide solid in vivo evidence that FGF10 acts as an important regulator of follicular growth in cattle.