The role of TGF-β superfamily members: TGF-β1 and activin A in early folliculogenesis

Abstract

Members of the TGF-β superfamily have been implicated in numerous roles throughout the process of folliculogenesis. They are expressed by oocytes, granulosa cells and theca cells and oversee follicle recruitment, growth, steroidogenesis, apoptosis, ovulation and luteinization (Knight and Glister, 2003). The importance of this family is well recognized and has formed the foundation of the research conducted throughout this PhD. To assess the role of members of the TGF-β superfamily play in folliculogenesis, more specifically from primordial to preantral follicle development, a model system of cultured whole ovaries was employed. The role of TGF-β1 and activin A in follicle development within the ovary was investigated. In the first instance, TGF-β1 was administered to cultured whole rat ovaries, with or without FSH. Follicle counts were performed and atresia was assessed. At the completion of these investigations the impact of activin A with or without FSH, on follicle development was assessed. Follicle counts were performed and an observation into atresia was made. The postnatal rat model employed has proven beneficial in investigating early follicle development as it utilizes the defined follicle populations that first appear in the ovary of the rodent. It allowed growth of these ovaries containing growing follicles with the addition of specific growth factors in order to assess the impact they may or may not be having on folliculogenesis (see Chapters 2 and 3). Additionally, Chapter 4 details the investigations made into the transgenic human follistatin (tghFST) mouse model. Follistatin (FST) is a monomeric protein that like inhibin, was initially discovered for its ability to suppress FSH activity (Robertson et al., 1987; Ueno et al., 1987). It is now well recognized that FST is a high-affinity activin-binding protein that can modulate the biological availability of activin (Nakamura et al., 1990). The two major isoforms, follistatin 288 (FST288) and follistatin 315 (FST315) result from alternative splicing of FST mRNA. Utilizing a novel “knock-in” approach of the tghFST genes, this mouse model expresses human FST288 and human FST315, providing a unique opportunity to decipher the differential roles each isoform may play in ovarian follicle development and growth. Whole organ histological and gene expression profiles were investigated. These studies have provided direct evidence for individual roles for healthy follicle development and growth. Further analysis will shed light into the interactions FST has with members of the TGF-β superfamily and its involvement in the pathway to female organogenesis. Ovarian follicle maturation is highly specialized involving various signalling factors, of which several belong to the TGF-β superfamily. Understanding how members of the TGF-β superfamily influence ovarian follicle development will greatly enhance our knowledge in ovarian and reproductive biology.