Postnatal regulation of germ cells by activin: The establishment of the initial follicle pool

Abstract

Mammalian females enter puberty with follicular reserves that exceed the number needed for ovulation during a single lifetime. Follicular depletion occurs throughout reproductive life and ends in menopause, or reproductive senescence, when the follicle pool is exhausted. The mechanisms regulating the production of a species-specific initial follicle pool are not well understood. However, the establishment of a follicular reserve is critical to defining the length of reproductive cyclicity. Here we show that activin A (rh-ActA), a known regulator of follicle formation and growth in vitro, increased the number of postnatal mouse primordial follicles by 30% when administered to neonatal animals during the time of germline cyst breakdown and follicle assembly. This expansion in the initial follicle pool was characterized by a significant increase in both germ cell and granulosa cell proliferation. However, the excess follicles formed shortly after birth did not persist into puberty and both adult rh-ActA- and vehicle-treated animals demonstrated normal fertility. A follicle atresia kinetic constant (k(A)) was modeled for the two groups of animals, and consistent with the empirical data, the k(A) for rh-ActA-treated was twice that of vehicle-treated animals. Kinetic constants for follicle formation, follicle loss and follicle expansion from birth to postnatal day 19 were also derived for vehicle and rh-ActA treatment conditions. Importantly, introduction of exogenous rh-ActA revealed an intrinsic ovarian quorum sensing mechanism that controls the number of follicles available at puberty. We propose that there is an optimal number of oocytes present at puberty, and when the follicle number is exceeded, it occurs at the expense of oocyte quality. The proposed mechanism provides a means by which the ovary eliminates excess follicles containing oocytes of poor quality prior to puberty, thus maintaining fertility in the face of abnormal hormonal stimuli in the prepubertal period.

Estrogen can signal through multiple pathways to regulate oocyte cyst breakdown and primordial follicle assembly in the neonatal mouse ovary

“…Activin was originally isolated based on its ability to stimulate the synthesis and secretion of FSH (de Kretser & Robertson 1989). Recently, it has been shown that activin promotes the establishment of the primordial follicle pool because neonatal activin treatment significantly increases the number of primordial follicles (Bristol-Gould et al 2006). Activin expression and downstream signaling are suppressed in neonatal ovaries exposed to estrogen (Kipp et al 2007).…”

Follicular assembly: mechanisms of action

“…Supporting the involvement of GDF9 in follicle formation, addition of GDF9 to hamster ovaries in organ culture promotes the formation of follicles (Wang & Roy 2004). Mouse ovaries exposed to another TGFB family member, activin A, have an increased number of primordial follicles (Bristol-Gould et al 2006). Supporting the role of activin in primordial follicle formation, more MOFs are observed in mice that overexpress the activin antagonist, inhibin B (McMullen et al 2001).…”

The role of TGF superfamily gene expression in the regulation of folliculogenesis and oogenesis in mammals: a review

“…Studies in rodents have revealed that steroids and members of the TGF superfamily, including GDF9 and BMP15, are involved in this process (Bristol-Gould et al 2006;Sanchez and Smitz 2012). The development of primary follicles to the late preantral and early antral stages involves follicular growth, fluid-filled antrum formation and oocyte enlargement and an increase in volume and size (Bachvarova et al 1985;Durinzi et al 1995;Eppig and O'Brien 1996;Picton et al 1998).…”