Ativina intraovariana: uma atualização sobre estrutura, regulação e função Intraovarian Activin: an Update on Structure, Regulation and Function

Background: Important advances have been made recently that clarify our understanding of the structural basis, signaling and regulation, as well as the biological role of activin in ovaries. During folliculogenesis various growth factors are produced locally in the mammalian ovary. Among these factors, activin has been a focal point in research as it has emerged as a crucial substance capable of inducing follicular development. The important actions indicate that activin has many relevant homeostatic functions in the reproduction of several species. Therefore, this review discusses the ligand protein structure, activin receptors, mechanisms of action and regulation, as well as the importance of activin on in vitro culture of preantral follicles. Review: Activin belongs to the transforming growth factor β (TGF - β) super family. It is a homodimer or heterodimer of two similar but distinct subunits (βA and βB). The dimerisation of activin subunits gives rise to three forms of activin, which are classifi ed as, activin A (βA - βA), activin B (βB - βB) and activin AB (βA - βB). The biological activity of activin occurs through its connection with two types of cell surface receptors designated type I and type II. These receptors are represented by two isoforms, activin receptor types IA (ActR - IA), IB (ActR - IB), IIA (ActR - IIA) and IIB (ActR IIB). Activin receptors are transmembrane proteins, composed of a ligand-binding extracellular domain, a transmembrane domain and a cytoplasmic domain with serine/threonine kinase activity. The transient activation of the receptor induces phosphorylation of protein mediators called Smads. Activation of Smad 2/3 by phosphorylation causes trimerization and hetero-oligomerization with the common Smad, Smad 4. This complex translocates to the nucleus to activating and regulating transcription of target genes. Members of another class of Smads act as negative regulators of the signal transduction pathway. Inhibitory Smad 7 can bind to type I receptors, preventing receptor‐Smad 2/3 association, or by competitively binding of Smad 4, which blocks Smad intracellular translocation. In addition, within the extracellular environment, binding proteins such as follistatin and inhibin can modulate the biological activity of activin. In the ovaries of mammals specifi cally, activin participates in several cellular events, including cellular proliferation, differentiation, and survival, as well as assisting steroidal hormones during follicular development. Activin has been localized in the oocytes and granulosa cells of rodent, porcine, caprine and bovine follicles. Activin is also within the granulosa cells of human follicles and in the thecal layers of porcine and human. In addition, activin stimulates follicle growth in-vitro, is used in pre-antral ovine and caprine follicles and enhances growth and survival of human pre-antral follicles in vitro. Conclusion: Activin is controlled by competitive substances and a dynamic interaction between the various regulatory proteins responsible for coordinating several signaling pathways. The balance between the actions of these proteins is critical for regulation of gene expression in different structures, including pre-antral follicles. However, the nature of physiological effects of activin in the ovary is still equivocal and awaits clarifi cation.