Platelet-derived growth factor modulates the primordial to primary follicle transition

Abstract

Primordial follicles steadily leave the arrested pool and undergo a primordial to primary follicle transition during the female reproductive lifespan. When the available pool of primordial follicles is depleted reproduction ceases and humans enter menopause. The present study was designed to investigate the actions of several growth factors previously identified as candidate regulatory factors for the primordial to primary follicle transition with a microarray analysis. Ovaries from 4-day-old rats were placed into culture and treated for 2 weeks with platelet-derived growth factor (PDGF), anti-PDGF neutralizing antibody, vascular endothelial growth factor (VEGF), neuregulin (NRG), or kit ligand (KITL) as a positive control. PDGF-treatment resulted in a significant decrease in the percentage of primordial follicles and a concomitant increase in the percentage of developing primary follicles compared to controls. In contrast, ovaries treated with an anti-PDGF neutralizing antibody had a significant increase in the percentage of primordial follicles demonstrating an inhibition of endogenous follicle development. Ovaries incubated in the presence of VEGF or NRG had no change in follicle development. Observations indicate that PDGF, but not VEGF or NRG, promotes the primordial to primary follicle transition. Immunohistochemical localization indicated that the PDGF protein was present in the oocytes of both primordial and developing follicles. PDGF-treatment of cultured ovaries resulted in an increase in KITL mRNA expression. KITL has been previously shown to promote the primordial to primary follicle transition. KITL-treatment of ovaries had no effect on expression of Pdgf or any PDGF homologs or receptors. Therefore, PDGF appears to be produced by the oocyte and acts as one of several extracellular signaling factors that regulate the primordial to primary follicle transition. These observations provide insight into the cell-cell interactions involved in the regulation of primordial follicle development and can be used in the future development of therapies for some forms of infertility.