NCBI Summary:
The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a motif of eight cysteines. This gene product can exist either as a homodimer or as a heterodimer with the platelet-derived growth factor beta polypeptide, where the dimers are connected by disulfide bonds. Studies using knockout mice have shown cellular defects in oligodendrocytes, alveolar smooth muscle cells, and Leydig cells in the testis; knockout mice die either as embryos or shortly after birth. Two splice variants have been identified for this gene.
General function
Ligand, Growth factor, Cell proliferation
Comment
Cellular localization
Other Membrane
Comment
Ovarian function
Preantral follicle growth
Comment
Pigment-Epithelium derived Factor (PEDF) and the human ovary: A role in the generation of ROS in granulosa cells. Kampfer C 2013 et al.
AIMS
Pigment Epithelium Derived Factor (PEDF) is a multifunctional factor, which was found in mouse ovary and in human ovarian follicular fluid (FF). Its ovarian functions include anti-angiogenic actions. This study aimed to explore other PEDF-actions and the sites of PEDF expression in the human ovary.
MATERIALS AND METHODS
We used paraffin-embedded human ovarian sections for PEDF-immunohistochemistry and IVF-derived human granulosa cells (GCs) for RT-PCR, Western blotting and functional studies, including measurement of cell viability (ATP-assay), apoptosis (caspase-assay) and reactive oxygen species (ROS).
KEY FINDINGS
Immunohistochemistry revealed PEDF in the cytoplasm of GCs of avascular follicles from the preantral to the antral stage and in FF. PEDF was also found in luteinized GCs of the highly vascularized corpus luteum, a result not in line with a sole anti-angiogenic action. Like GCs in vivo, cultured human luteinizing GCs express PEDF. They also responded to exogenous recombinant PEDF. In low concentrations PEDF did not affect cell viability but caused generation ROS. ROS-induction by PEDF was a concentration-dependent process and may be due to the activity of NADPH oxidase (NOX) type 4 and/or 5, which as we found are expressed by GCs. An antioxidant and apocynin, which inhibits NOX, blocked ROS generation. High levels of exogenous recombinant PEDF induced apoptosis of GCs, which was prevented by antioxidants, implying involvement of ROS.
SIGNIFICANCE
PEDF is emerging as an ovarian factor, which has unexpected ROS-augmenting activities in the human ovary. It may be involved in ovarian ROS homeostasis and may contribute to oxidative stress.
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Expression Levels of mRNA-Encoding PDGF Receptors in Goat Ovaries and the Influence of PDGF on the In Vitro Development of Caprine Pre-Antral Follicles. Brito I et al. The aims of this study were to investigate the expression levels of mRNA for platelet-derived growth factor (PDGF) receptors (PDGFR-a and -? in caprine follicles at different developmental stages and to evaluate the influence of PDGF on the in vitro development of pre-antral follicles. For this, goat primordial, primary and secondary follicles, as well as small (1-3 mm) and large (3-6 mm) antral follicles, were obtained, and PDGFR-a and -?mRNA levels were quantified by real-time PCR. Furthermore, pre-antral follicles (=200 ?m) were isolated from goat ovaries and cultured for 18 days in a- minimum essential medium supplemented with PDGF at 50 or 100 ng/ml, containing or not FSH. Real-time PCR showed highest PDGFR-a mRNA levels in secondary follicles, while PDGFR-?mRNA levels were highest in primary follicles onwards. Both receptors showed higher mRNA levels in granulosa/theca cells from small and large antral follicles than in their corresponding cumulus-oocyte complexes. In culture, the percentage of antrum formation was significantly higher in 100 ng/ml PDGF compared with the same PDGF concentration associated with FSH. After 18 days, PDGF in both concentrations associated with FSH promoted follicular growth significantly higher than the control. Moreover, the addition of FSH to 50 ng/ml PDGF positively influenced the follicular growth when compared with the same PDGF concentration in the absence of FSH. In conclusion, PDGF is important for early goat folliculogenesis, because the presence of PDGFR-a and -?mRNA was detected in all follicular categories, and PDGF associated with FSH stimulated the growth of goat pre-antral follicles isolated and cultured in vitro.
Expression regulated by
Comment
BMP-specific SMADs function as novel repressors of PDGFA and modulate its expression in ovarian granulosa cells and tumors. Tripurani SK et al. Platelet-derived growth factor alpha (PDGFA) is frequently upregulated in various cancers and thought to function as a key player in the development and progression of tumor growth by regulating aspects of cell proliferation, angiogenesis and metastasis. However, the mechanism by which it is upregulated is not fully understood. Previously, we demonstrated that conditional deletion of two transcription factors that signal for the bone morphogenetic proteins (Smad1 and Smad5) in ovarian granulosa cells causes metastatic granulosa cell tumors (GCTs) in female mice and phenocopies human juvenile GCTs (JGCTs). Smad1/5 double conditional knockout tumors, as well as human JGCTs, are highly vascularized, hemorrhagic and mitotically active. Expression analysis of these tumors and their metastases revealed a significant upregulation of key proliferation and pro-angiogenic factors such as Pdgfa, Pdgfb and Vegf. We examined whether these genes were direct targets of SMAD1 and SMAD5. Knockdown of SMAD1 and SMAD5 in mouse primary granulosa cells and a human GCT-derived cell line (COV434) resulted in upregulation of PDGFA, but not PDGFB nor VEGF. We identified several putative SMAD1/5-binding sites in the PDGFA promoter, and chromatin immunoprecipitation and reporter assays demonstrated that SMAD1/5 interact with the PDGFA promoter to regulate its activity. Further, SMAD1/5 antagonize the activity of the transcription factor Sp1, a well-known positive regulator of PDGFA, by inhibiting its occupancy at a key regulatory site on the proximal PDGFA promoter. Collectively, our studies establish that loss of SMAD1/5 leads to upregulation of PDGFA in ovarian granulosa cells, and that a novel regulatory interaction exists between the BR-SMADs and Sp1 in controlling PDGFA expression during granulosa cell tumorigenesis.Oncogene advance online publication, 10 September 2012; doi:10.1038/onc.2012.392.
Ovarian localization
Oocyte, Granulosa
Comment
This gene was found in a mouse DNA array analysis of transcripts expressed in mouse preovulatory follicles. Okamura Y, et al., (2001) studied the protein tyrosine kinase expression in the porcine ovary. Clones for the porcine homologues of platelet-derived growth factor receptor alpha (PDGFRalpha) and of insulin-like growth factor-I receptor (IGF-IR) were found during follicle growth both in oocytes and follicle cells. Clones for the porcine homologues of focal adhesion kinase (FAK), of c-kit and of fms-like tyrosine kinase (FLT)-3 were found only in oocytes. Moreover, after 24 h of in-vitro maturation of the cumulus-oocyte complexes, clones for the porcine homologues of FLT-1, of FLT-4, of Tie2 and of RYK in oocytes were observed. Immunohistochemical studies revealed the existence of PDGFRalpha, platelet-derived growth factor A (PDGFA), FAK and FLT3 in oocytes at various stages of folliculogenesis. These results suggest that fluctuations in the expression of these PTK genes may be involved in follicle growth and maturation.
Follicle stages
Comment
Platelet-derived growth factors (PDGF-A and B) and their receptors in human fetal and adult ovaries. Pinkas H et al. There is no information regarding the presence of platelet-derived growth factors (PDGFs) and their receptors in human ovaries. The expression of PDGF-A, PDGF-B, and their two receptors, PDGFR-alpha and PDGFR-beta, was investigated in ovarian samples from women/girls and from human fetuses, at the protein and mRNA levels. The samples were prepared for immunohistochemical staining for PDGF-A and PDGF-B and their two receptors and in situ hybridization for the detection of the mRNA transcripts of the receptors. Total RNA was extracted from frozen ovarian samples, and the expression of PDGF-A and PDGF-B was investigated by reverse transcription polymerase chain reaction. The proteins for PDGF-A and PDGF-B were detected in oocytes, and in granulosa cells (GC) of 50% of the follicles from women/girls. The proteins and mRNA transcripts for the two receptors were detected in oocytes (mRNA for PDGFR-beta only in 25% of the oocytes). PDGFR-alpha mRNA was expressed in GC of a minority of the samples from women/girls, whereas PDGFR-beta protein and mRNA were identified in over 50% of the GC from this source. PDGF-A and -B transcripts were identified in all the extracts. The presence of the receptors in GC suggests that PDGFs might be involved in the activation of primordial follicles.