Roles for transforming growth factor beta superfamily proteins in early folliculogenesis

Abstract

Primordial follicle formation and the subsequent transition of follicles to the primary and secondary stages encompass the early events during folliculogenesis in mammals. These processes establish the ovarian follicle pool and prime follicles for entry into subsequent growth phases during the reproductive cycle. Perturbations during follicle formation can affect the size of the primordial follicle pool significantly, and alterations in follicle transition can cause follicles to arrest at immature stages or result in premature depletion of the follicle reserve. Determining the molecular events that regulate primordial follicle formation and early follicle growth may lead to the development of new fertility treatments. Over the last decade, many of the growth factors and signaling proteins that mediate the early stages of folliculogenesis have been identified using mouse genetic models, in vivo injection studies, and ex vivo organ culture approaches. These studies reveal important roles for the transforming growth factor beta (TGF-beta) superfamily of proteins in the ovary. This article reviews these roles for TGF-beta family proteins and focuses in particular on work from our laboratories on the functions of activin in early folliculogenesis.

Figure 1

(A) Transforming growth factor beta (TGF-β) family cell signaling pathway. TGF-β family ligands bind and signal through serine/threonine kinase receptors on the plasma membrane. Signals are transduced through phosphorylated receptor Smad proteins. Receptor Smad/co-Smad dimers translocate into the nucleus to stimulate target gene transcription. (B) Receptors and Smad proteins that comprise the core signaling pathway for TGF-β and bone morphogenetic proteins (BMP) family ligands. See Shimasaki et al for a comprehensive list of TGF-β family ligands and their receptors. AMH, anti-müllerian hormone; GDF, growth differentiation factors.

Figure 2

Hormonal regulation of germ cell nest breakdown. (A) Germ cell nests breakdown giving rise to primordial follicles. (B) Increased activin (act) signaling within neonatal mouse ovaries leads to a higher number of primordial follicles compared with controls. (C) Increased estradiol (E₂) signaling within neonatal mouse ovaries downregulates activin expression and results in multi-oocytic follicle (MOF) formation.

Figure 3

Early folliculogenesis involves the breakdown of germ cell nests into primordial follicles and the subsequent transition of follicles to the primary and secondary stages. Different transforming growth factor beta (TGF-β) superfamily ligands regulate each of these developmental processes. Activin may play a role in primordial follicle formation. Bone morphogenetic protein 7 (BMP7) and BMP4 promote the transition of primordial follicles to primary follicles, whereas anti-müllerian hormone (AMH) inhibits initial follicle growth. Growth differentiation factor 9 (GDF9) is critical for follicles to advance to the secondary stage. In primary follicles, inhibin may be suppressed by GDF9, which allows for granulosa cell proliferation by activin. Bars indicating the relative activities of these TGF-β family proteins in prepubertal mouse ovaries are also shown (black = high activity). E₂, estradiol.