TGF-β superfamily members and ovarian follicle development

Abstract

In recent years, exciting progress has been made towards unravelling the complex intraovarian control mechanisms that, in concert with systemic signals, coordinate the recruitment, selection and growth of follicles from the primordial stage through to ovulation and corpus luteum formation. A plethora of growth factors, many belonging to the transforming growth factor-b (TGF-b) superfamily, are expressed by ovarian somatic cells and oocytes in a developmental, stage-related manner and function as intraovarian regulators of folliculogenesis. Two such factors, bone morphogenetic proteins, BMP-4 and BMP-7, are expressed by ovarian stromal cells and/or theca cells and have recently been implicated as positive regulators of the primordial-to-primary follicle transition. In contrast, evidence indicates a negative role for anti-Mullerian hormone (AMH, also known as Mullerianinhibiting substance) of pre-granulosa/granulosa cell origin in this key event and subsequent progression to the antral stage. Two other TGF-b superfamily members, growth and differentiation factor-9 (GDF-9) and BMP-15 (also known as GDF-9B) are expressed in an oocyte-specific manner from a very early stage and play key roles in promoting follicle growth beyond the primary stage; mice with null mutations in the gdf-9 gene or ewes with inactivating mutations in gdf-9 or bmp-15 genes are infertile with follicle development arrested at the primary stage. Studies on later stages of follicle development indicate positive roles for granulosa cell-derived activin, BMP-2, -5 and -6, theca cell-derived BMP-2, -4 and -7 and oocyte-derived BMP-6 in promoting granulosa cell proliferation, follicle survival and prevention of premature luteinization and/or atresia. Concomitantly, activin, TGF-b and several BMPs may exert paracrine actions on theca cells to attenuate LH-dependent androgen production in small to medium-size antral follicles. Dominant follicle selection in monovular species may depend on differential FSH sensitivity amongst a growing cohort of small antral follicles. Changes in intrafollicular activins, GDF-9, AMH and several BMPs may contribute to this selection process by modulating both FSH-and IGF-dependent signalling pathways in granulosa cells. Activin may also play a positive role in oocyte maturation and acquisition of developmental competence. In addition to its endocrine role to suppress FSH secretion, increased output of inhibin by the selected dominant follicle(s) may upregulate LH-induced androgen secretion that is required to sustain a high level of oestradiol secretion during the pre-ovulatory phase. Advances in our understanding of intraovarian regulatory mechanisms should facilitate the development of new approaches for monitoring and manipulating ovarian function and improving fertility in domesticated livestock, endangered species and man.

Anti-Müllerian hormone is produced heterogeneously in primate preantral follicles and is a potential biomarker for follicle growth and oocyte maturation in vitro

“…Coexpressed with its receptor, AMH appears to be an autocrine factor in regulating primate ovarian follicular development. This stage-dependent expression of a ligand and its receptor has been noted for other TGFβ superfamily members in human follicles [37]. Studies are ongoing to further unravel the molecular mechanisms of AMH signaling in the primate follicle by gene silencing.…”

The crucial role of Activin A on the formation of primordial germ cell-like cells from skin-derived stem cells in vitro

“…53,54 Members of this family have important roles in proliferation, differentiation, adhesion, motility and apoptosis. Many are involved in embryonic development as well as in adult tissue homeostasis.…”

Follicle-stimulating hormone isoforms and plasma concentrations of estradiol and inhibin A in dairy cows with ovulatory and non-ovulatory follicles during the first postpartum follicle wave

“…In the current study, we observed an increase in less acidic FSH isoforms during the final stages of follicle development in cows with an ovulatory follicle, associated with significantly greater circulating inhibin A and estradiol concentrations. Increased output of inhibin by the selected dominant follicle may upregulate LH-induced androgen secretion that is required to sustain a high level of 210 estradiol secretion from the preovulatory follicle (30).…”

“…A prompt resumption of ovulatory activity following parturition is desirable; cows that have an early commencement of luteal activity have an improved likelihood of conception after breeding (4). 30 Timing of the first postpartum ovulation is correlated with timing of the onset of recovery from the negative energy balance (NEB) nadir (5,6). Infusion of exogenous pulses of LH during the first postpartum follicle wave in dairy (7) and beef (8) cows increased the likelihood of ovulation.…”