GDF-9 and BMP-15 direct the follicle symphony

Abstract

Understanding the physiology underlying the complex dialog between the oocyte and its surrounding somatic cells within the ovarian follicle has been crucial in defining optimal procedures for the development of clinical approaches in ART for women suffering from infertility and ovarian dysfunction. Recent studies have implicated oocyte-secreted factors like growth differentiation factor 9 (GDF-9) and bone morphogenetic protein 15 (BMP-15), members of the transforming growth factor-beta (TGFβ) superfamily, as potent regulators of folliculogenesis and ovulation. These two factors act as biologically active heterodimers or as homodimers in a synergistic cooperation. Through autocrine and paracrine mechanisms, the GDF-9 and BMP-15 system has been shown to regulate growth, differentiation, and function of granulosa and thecal cells during follicular development playing a vital role in oocyte development, ovulation, fertilization, and embryonic competence. The present mini-review provides an overview of recent findings relating GDF-9 and BMP-15 as fundamental factors implicated in the regulation of ovarian function and discusses their potential role as markers of oocyte quality in women.

Keywords: BMP-15; Folliculogenesis; GDF-9; Oocyte quality; Ovarian function; TGFβ.

Fig. 1

Paraffin sections of P2, P8, and P20 ovaries in GDF-9 heterozygous (a, b, c) and GDF-9 KO mice (d, e, f). Stereoscopic images showing the phenotype of the GDF-9 KO mice: absence of secondary follicles (f), activation of the follicular reserve (d), and oocyte continuing growth (f)

Fig. 2

Paraffin sections of P2 and P8 mouse ovaries stained for a microtubule marker, acetylated-tubulin (green), and a gap-junction marker, connexin-43 (red), in GDF-9 Heterozygous (a, c) and GDF-9 KO mice (b, d). It is possible to observe irregular gap junction distribution among the GDF-9 KO ovaries (b–d) within preganulosa and granulosa cells and the absence of secondary or graffian follicles

Fig. 3

Schematic diagram exhibiting the functional roles of the main TGF-β superfamily member proteins in regulating ovarian function. GDF-9 and BMP-15 are implicated in the transition of the primordial follicle to the primary follicle stage. In theca cells BMP-7 regulates VEGF and thus the flow of nutrients within the follicle. GCs contribute to oocyte antioxidant defense against reactive oxygen species (ROS) [118] and to oocyte nutrients through glycolysis and cholesterol biosynthesis which is regulated by oocyte-derived GDF-9 and BMP-15. The paracrine interactions between BMP-15 and KITL are an example of a negative feedback system: while oocyte-derived BMP-15 induces KITL expression in granulosa cells, KITL from granulosa cells inhibits BMP-15 secretion by the oocyte. Overall, the roles of GDF-9 and BMP-15 are evidenced in regulating the function of GCs, GC communication, COC expansion and hyaluronan production leading to ovulation, and in preventing luteinization through inhibition of progesterone production