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 is a potent epithelial cell-specific growth factor, whose mitogenic activity is predominantly exhibited in keratinocytes but not in fibroblasts and endothelial cells. Studies of mouse and rat homologs of this gene implicated roles in morphogenesis of epithelium, reepithelialization of wounds, hair development and early lung organogenesis. [provided by RefSeq, Jul 2008]
General function
Ligand, Growth factor
Comment
Cross Talk between KGF and KITLG Proteins Implicated with Ovarian Folliculogenesis in Buffalo Bubalus bubalis. Panwar D et al. (2015) Molecular interactions between mesenchymal-derived Keratinocyte growth factor (KGF) and Kit ligand (KITLG) are essential for follicular development. These factors are expressed by theca and granulosa cells. We determined full length coding sequence of buffalo KGF and KITLG proteins having 194 and 274 amino acids, respectively. The recombinant KGF and KITLG proteins were solubilized in 10 mM Tris, pH 7.5 and 50 mM Tris, pH 7.4 and purified using Ni-NTA column and GST affinity chromatography, respectively. The purity and molecular weight of His-KGF (~23 kDa) and GST-KITLG (~57 kDa) proteins were confirmed by SDS-PAGE and western blotting. The co-immunoprecipitation assay accompanied with computational analysis demonstrated the interaction between KGF and KITLG proteins. We deduced 3D structures of the candidate proteins and assessed their binding based on protein docking. In the process, KGF specific residues, Lys123, Glu135, Lys140, Lys155 and Trp156 and KITLG specific ones, Ser226, Phe233, Gly234, Ala235, Phe236, Trp238 and Lys239 involved in the formation of KGF-KITLG complex were detected. The hydrophobic interactions surrounding KGF-KITLG complex affirmed their binding affinity and stability to the interacting interface. Additionally, in-silico site directed mutagenesis enabled the assessment of changes that occurred in the binding energies of mutated KGF-KITLG protein complex. Our results demonstrate that in the presence of KITLG, KGF mimics its native binding mode suggesting all the KGF residues are specific to their binding complex. This study provides an insight on the critical amino acid residues participating in buffalo ovarian folliculogenesis.//////////////////
Cellular localization
Secreted
Comment
Ovarian function
Initiation of primordial follicle growth, Preantral follicle growth, Oocyte growth
Comment
Keratinocyte growth factor promotes the survival, growth, and differentiation of preantral ovarian follicles. McGee EA et al. OBJECTIVE: To determine the effect of treatment with keratinocyte growth factor (KGF) on the survival of cells in cultured preantral follicles and on the growth and differentiation of preantral follicles. DESIGN: Preantral follicles (140-150 microm) were dissected mechanically from the ovaries of 14-day-old rats and cultured for 24 hours with and without KGF. Genomic DNA was extracted, labeled with 32P-dideoxyadenosine triphosphate, and fractionated through agarose gels. For growth studies, the follicles were cultured individually in 96-well dishes. After 72 hours, the follicles were collected and their protein or DNA content was evaluated and their inhibin-alpha content was determined. RESULT(S): Keratinocyte growth factor suppressed apoptosis in cultured preantral follicles by 60%. Treatment with KGF or FSH increased follicle diameter by 8% and 16%, respectively, and combined treatment with KGF and FSH increased follicle diameter by 26%. Western blot analysis demonstrated increased expression of inhibin-alpha content after treatment with KGF (2-fold), treatment with FSH (4-fold), and combined treatment with FSH and KGF (12-fold), demonstrating the effect of KGF on preantral follicle differentiation. CONCLUSION(S): Treatment with KGF promotes the survival, growth, and differentiation of cultured preantral follicles. Keratinocyte growth factor produced by theca cells may play a role in the progression of early follicle development.
Keratinocyte Growth Factor Acts as a Mesenchymal Factor that Promotes Ovarian Primordial to Primary Follicle Transition Kezele P, et al .
An important but poorly understood process in ovarian biology is the transition of the developmentally arrested primordial follicle to the developing primary follicle. Interactions between the epithelial and mesenchymal cells of the follicle are critical for the coordination of ovarian follicle development. The mesenchymal growth factor keratinocyte growth factor (KGF) (i.e. fibroblast growth factor-7, FGF7) and the epithelial growth factor Kit Ligand (KITL) are known to interact to coordinate the growth of later stage antral follicles. The hypothesis tested in the current study is that KGF acts as a mesenchymal factor to promote the primordial to primary follicle transition. A postnatal 4-day-old rat ovary organ culture system was used to investigate the actions of KGF. KGF treatment promoted 65% of follicles to undergo the primordial to primary follicle transition, while only 45% undergo development in control ovaries. Neutralizing antibody for KGF was found to attenuate the stimulatory action of KITL, but neutralizing antibody for KITL was not able to attenuate the stimulatory action of KGF. Further analysis demonstrated that KGF was found to stimulate the expression of KITL (i.e. mRNA levels) by granulosa cells. KITL in turn was found to stimulate the expression of KGF to create a positive feedback loop. Interestingly, KGF expression was localized to selected mesenchymal cells (i.e. precursor theca cells) surrounding the developing primordial follicle. Observations suggest developing granulosa cells of the primordial follicles produce KITL that helps recruit precursor theca cells to the follicle that then produce KGF that acts on the granulosa to amplify KITL expression and support primordial follicle development. KGF appears to be a mesenchymal factor that promotes the primordial to primary follicle transitions.
Fibroblast growth factor 7 stimulates in vitro growth of oocytes originating from bovine early antral follicles. Cho JH et al. Essential factors required for growing oocytes derived from bovine early antral follicles and their mechanisms of action are poorly understood. Fibroblast growth factor 7 (FGF7) is a member of the heparin-binding FGF family with a distinctive pattern of target-cell specificity. The effect of FGF7 on the stimulation of oocyte growth in a culture of cumulus-oocyte complexes with granulosa cells (COCGs, oocyte diameter; 90-100 microm) was investigated. The oocyte diameter of COCGs was increased significantly in the FGF7-containing medium (10 ng/ml; 117.2 +/- 3.2 microm, 50 ng/ml; 116.5 +/- 3.5 microm) compared to the control (0 ng/ml; 110.5 +/- 2.8 microm) after 16 days. However, there was no stimulatory effect of FGF7 on the proliferation of cumulus-granulosa cells. The FGF7 receptor, fibroblast growth factor receptor 2IIIb (FGFR2IIIb), was detected in cumulus-granulosa cells from COCGs. Messenger RNA expression of FGFR2IIIb was induced to cumulus-granulosa cells by FGF7. The mRNA expression levels of KIT ligand (KITLG), KIT (KIT), growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) in the cultured COCGs were determined in FGF7-treated (10 ng/ml) cultures using real time RT-PCR analysis. The levels of KITLG and KIT, but not GDF9 and BMP15 mRNA expression were stimulated by FGF7. Furthermore, neutralizing antibody for KIT attenuated the stimulatory action of FGF7 on the oocyte growth. These results strongly suggest that FGF7 may be an important regulator for oocyte growth and its action is mediated via the KIT/KITLG signaling pathway. Mol. Reprod. Dev. (c) 2008 Wiley-Liss, Inc.
Keratinocyte growth factor and its receptor in human ovaries from fetuses, girls and women. Abir R et al. Keratinocyte growth factor (KGF) promotes growth of rat preantral follicles. There is limited information regarding its presence or that of its unique receptor (KGFR) in human ovaries, specifically in preantral follicles. The aim of the study was to investigate the expression of KGF and KGFR in ovarian samples from human fetuses and girls/women. The samples were prepared for immunohistochemical study of the KGF protein and for in situ hybridization to localize mRNA transcripts of KGFR. Total RNA was extracted from frozen ovarian samples, and the expression of KGF mRNA transcripts was investigated by reverse transcriptase polymerase chain reaction. In both fetuses and girls/women the protein for KGF was detected from primordial stages in oocytes, granulosa cells, and stroma cells. Its mRNA transcripts were also detected in all extracts. The mRNA transcripts for KGFR were detected mainly in stroma cells in ovarian samples from both sources; in 10% of the samples, follicular staining was noted also in oocytes and granulosa cells. Further studies adding KGF to the culture medium are needed to elucidate its putative role in human primordial follicle activation.
Expression of Keratinocyte Growth Factor in Goat Ovaries and Its Effects on Preantral Follicles Within Cultured Ovarian Cortex. Faustino LR et al. The aims of this study were to evaluate the expression of keratinocyte growth factor (KGF) in goat ovaries and to study its effects on preantral follicle survival and development. The ovaries were used for immunohistochemistry or for in vitro culture for 1 or 7 days with KGF (0, 1, 10, 50, 100, 150, or 200 ng/mL). Noncultured (fresh control) and cultured ovarian slices were processed for histological analysis and transmission electron microscopy (TEM). The results showed that after 7 days of in vitro culture, all treatments had a significant reduction in the percentage of normal follicles compared with the fresh control. After 7 days of culture, the highest KGF concentrations (150 and 200 ng/mL) induced a significant reduction in the percentage of normal follicles compared with the tissues cultured in the absence (a-MEM(+) alone) or presence of 1, 10, and 50 ng/mL KGF. Transmission electron microscopy confirmed follicular integrity after 7 days of culture in 1 ng/mL KGF. In addition, compared with the fresh control, the percentage of growing follicles was significantly increased in all treatments after 1 or 7 days of culture. Immunohistochemical analyses showed the expression of KGF in oocytes and granulosa cells in all follicle developmental stages as well as in thecal and stromal cells. In conclusion, this study demonstrated that, at the lowest concentration (1 ng/mL), KGF maintained the ultrastructure of goat preantral follicles cultured in vitro for up to 7 days. Furthermore, the KGF protein was widely distributed in goat ovaries, especially in ovarian follicles.
Expression regulated by
Comment
Ovarian localization
Granulosa, Theca
Comment
Berisha B, et al reported the expression and localization of fibroblast growth factor (FGF) family members during the final growth of bovine ovarian follicles.
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The aim of this study was to investigate the possible participation of fibroblast growth factor (FGF) family members: FGF1, FGF2, and FGF7, and their receptor variants: FGFR, FGFR2IIIb, and FGFR2IIIc in theca interna (TI) and granulosa cell (GC) compartments of bovine follicles during final growth. A classification of follicles into five groups (<0.5; >0.5-5; >5-20; >20-180; >180 ng/ml, respectively) was performed according to the follicular fluid (FF) oestradiol-17beta (E) content. The mRNA expression and protein localization was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. FGF1 mRNA expression was relatively high in TI and lower in GC, and without any regulatory change for both tissue compartments during final follicular growth. The FGF1 protein could be predominantly localized in the cytoplasm of GC, in smooth muscle cells of blood vessels, in the rete ovarii, and at a lesser degree in theca cells. FGF2 mRNA in TI increased significantly in large follicles and was low and without any regulatory change in GC. FGF7 mRNA expression was relatively high in TI and very low in GC. For FGF7 in mature follicles a marked staining of the TI and the basal layers of the GC could be demonstrated. The mRNA signal for the FGFR in TI increased significantly with beginning of E production (E > 0.5-5 ng/ml FF) and was without any regulatory change in GC. The mRNA expression of FGFR2IIIb was relatively high in GC and increased significantly during final growth of follicles in contrast to the TI with very low expression. The FGFR2IIIc mRNA expression in TI and GC was relatively high but without any clear change. Our results suggest that FGF growth factor family members are involved in process of folliculogenesis and especially during final growth of the preovulatory (dominant) follicle by stimulation of angiogenesis and GC survival and proliferation.
Follicle stages
Antral, Corpus luteum
Comment
Expression of Fibroblast Growth Factor 1 (FGF1) and FGF7 in Mature Follicles during the Periovulatory Period after GnRH in the Cow Berisha B, e al .
The aim of this study was to evaluate the expression pattern of mRNA for fibroblast growth factor 1 (FGF1), FGF7, and their receptor variants (FGFR2IIIb) in time-defined follicle classes before LH surge, between LH surge and ovulation, and in the early corpus luteum (CL) in the cow. The ovaries were collected by transvaginal ovariectomy (n=5 cows/group), and the follicles (n=5, one follicle/cow) were classified into the following groups: before GnRH administration (before LH surge); 3-5 h after GnRH (during LH surge); 10 h after GnRH; 20 h after GnRH; 25 h after GnRH (periovulation), and early CL (Days 2-3). The mRNA expression was analyzed by quantitative real-time PCR (RotorGene 3000). The mRNA expression of FGF1 showed no significant differences in the follicle groups examined, but increased significantly at the early CL phase. A transient increase in FGF7 mRNA expression was observed 3-5 h after GnRH and again in the early CL phase. In contrast, the expression of FGFR2IIIb was constant throughout the period from the final growth of the follicle to early CL formation. The results of this study suggest that FGF1 and FGF7 may be involved differently in the process of follicle maturation and CL formation, which is strongly dependent on angiogenesis.