The molecular cloning of the signal transducing receptors for fibroblast growth
factors has revealed a tyrosine kinase gene family with at least four members.
Differential splicing and polyadenylation creates further diversity in the FGF
receptor system. These numerous receptor forms have both distinct and redundant
properties.
NCBI Summary:
The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. Alternative splicing occurs and additional variants have been described, including those utilizing alternate exon 8 rather than 9, but their full-length nature has not been determined.
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Steroid metabolism
Comment
Expression regulated by
FSH
Comment
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Abraham Amsterdam, et al 2001 reported apoptosis of Granulosa Cells and Female Infertility in Achondroplastic
Mice Expressing Mutant Fibroblast Growth Factor Receptor 3G374R.
The normal ovary consists mainly of healthy
corpora lutea
and follicles at different stages of development.
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.
Follicle stages
Preovulatory
Comment
Expression of fibroblast growth factor-8 and regulation of cognate receptors, fibroblast growth factor receptor-3c and -4, in bovine antral follicles Buratini J Jr, et al .
Paracrine cell signaling is believed to be important for ovarian follicle development, and a role for some members of the fibroblast growth factor (FGF) family has been suggested. In the present study, we tested the hypothesis that FGF-8 and its cognate receptors (FGFR3c and FGFR4) are expressed in bovine antral follicles. RT-PCR was used to analyze bovine Fgf8, Fgfr3c and Fgfr4 mRNA levels in oocytes, and granulosa and theca cells. Fgf8 expression was detected in oocytes and in granulosa and theca cells; this expression pattern differs from that reported in rodents. Granulosa and theca cells, but not oocytes, expressed Fgfr3c, and expression in granulosa cells increased significantly with follicle estradiol content, a major indicator of follicle health. Fgfr4 expression was restricted to theca cells in the follicle, and decreased significantly with increasing follicle size. To investigate the potential regulation of Fgfr3c expression in the bovine granulosa, cells were cultured in serum-free medium with FSH or IGF-I; gene expression was upregulated by FSH but not by IGF-I. The FSH-responsive and developmentally regulated patterns of Fgfr3c mRNA expression suggest that this receptor is a potential mediator of paracrine signaling to granulosa cells during antral follicle growth in cattle.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: targeted overexpression fertility: infertile - non-ovarian defect Comment:Abraham Amsterdam, et al 2001 reported apoptosis of Granulosa Cells and Female Infertility in Achondroplastic
Mice Expressing Mutant Fibroblast Growth Factor Receptor 3G374R.
The most common form of inherited human
dwarfism
results from a point mutation in the transmembrane region of fibroblast growth
factor receptor 3. A mouse model for achondroplasia was generated by
introducing
the human mutation (glycine 380-arginine) into the mouse fibroblast growth
factor receptor 3 (G374R) by a "knock-in" approach using gene targeting
leading to a
constitutively active receptor. This resulted in the development of dwarf mice
that share many features with human achondroplasia. While
no significant changes were observed in the anatomical and histological
appearance
of ovaries of 3-wk-old dwarf mice, a dramatic difference was observed in
ovaries of 3-month-old mice.
The normal ovary consists mainly of healthy
corpora lutea
and follicles at different stages of development, whereas the ovaries of the
dwarf mice remain small and contain mainly follicles with a progressive
apoptosis in the
granulosa cells, and no corpora lutea could be observed. The levels of LH,
FSH, and progesterone were lower by 72.3%, 38.0%, and 40.0%, respectively, in
the
blood of the dwarf mice compared with normal mice, and the total bioactivity
of pituitary FSH and LH was lower by 65.6% and 79.6%, respectively, in the
dwarf
mice compared with normal mice. However treatment with PMSG and human CG of
the dwarf mice led to rapid follicular development and formation of corpora
lutea. Interestingly, the expression of the tumor suppressor gene p53 was
increased dramatically in ovaries of the dwarf mice. The presence of the
fibroblast growth
factor receptor 3 cellular receptors in both normal and dwarf animals was
demonstrated by Western blot and immunostaining. However, the distribution of
the
fibroblast growth factor receptors in the two strains shows significant
differences. In the normal ovaries fibroblast growth factor receptor 3 was
homogeneously
distributed on the cell membrane of the granulosa cells and was absent in theca as well as corpora lutea cells, whereas in dwarf mice ovaries it was highly clustered on granulosa cells and very often appears in endocytic vesicles. Aged oocytes
were more frequently observed in preantral follicles of ovaries of the dwarf
mice.
Nevertheless, oocytes isolated from antral follicles resume their meiotic
division at a high percentage, similar to oocytes obtained from normal
ovaries. The results
imply fibroblast growth factor receptor 3 involvement in the control of
follicular development through regulation of granulosa cell growth and
differentiation, and that
unovulation in the dwarf mice could be overcome in part by administration of
exogenous gonadotropins.