Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium

Abstract

It has been 70 years since the name inhibin was used to describe a gonadal factor that negatively regulated pituitary hormone secretion. The majority of this period was required to achieve purification and definitive characterization of inhibin, an event closely followed by identification and characterization of activin and follistatin (FS). In contrast, the last 15–20 years saw a virtual explosion of information regarding the biochemistry, physiology, and biosynthesis of these proteins, as well as identification of activin receptors, and a unique mechanism for FS action—the nearly irreversible binding and neutralization of activin. Many of these discoveries have been previously summarized; therefore, this review will cover the period from the mid 1990s to present, with particular emphasis on emerging themes and recent advances. As the field has matured, recent efforts have focused more on human studies, so the endocrinology of inhibin, activin, and FS in the human is summarized first. Another area receiving significant recent attention is local actions of activin and its regulation by both FS and inhibin. Because activin and FS are produced in many tissues, we chose to focus on a few particular examples with the most extensive experimental support, the pituitary and the developing follicle, although nonreproductive actions of activin and FS are also discussed. At the cellular level, it now seems that activin acts largely as an autocrine and/or paracrine growth factor, similar to other members of the transforming growh factor β superfamily. As we discuss in the next section, its actions are regulated extracellularly by both inhibin and FS. In the final section, intracellular mediators and modulators of activin signaling are reviewed in detail. Many of these are shared with other transforming growh factor β superfamily members as well as unrelated molecules, and in a number of cases, their physiological relevance to activin signal propagation remains to be elucidated. Nevertheless, taken together, recent findings suggest that it may be more appropriate to consider a new paradigm for inhibin, activin, and FS in which activin signaling is regulated extracellularly by both inhibin and FS whereas a number of intracellular proteins act to modulate cellular responses to these activin signals. It is therefore the balance between activin and all of its modulators, rather than the actions of any one component, that determines the final biological outcome. As technology and model systems become more sophisticated in the next few years, it should become possible to test this concept directly to more clearly define the role of activin, inhibin, and FS in reproductive physiology.

A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene

“…Activins are key modulators of follistatin expression and many tissues that express and respond to activin often also produce follistatin (2,7). This close anatomic and functional link establishes a local feedback loop that safeguards against excessive activin signaling and insures that the necessary balance of activin and follistatin tone within a given tissue is maintained.…”

“…This close anatomic and functional link establishes a local feedback loop that safeguards against excessive activin signaling and insures that the necessary balance of activin and follistatin tone within a given tissue is maintained. Accordingly, it is presumed that many of the demonstrated actions of follistatins reflect their influence as local "buffers" of the bioactivity of activins and other members of the TGF-␤ family of ligands (2,14). In the anterior pituitary, the self-modulating mechanism through which activin induces follistatin production exerts control over activin bioactivity and plays a pivotal role in maintaining FSH␤ expression and FSH production from gonadotropes at levels that are physiologically relevant and necessary for normal reproductive function (7,8).…”

“…Activins are members of the evolutionarily conserved transforming growth factor-␤ (TGF-␤) 3 superfamily of factors implicated in the control of a wide array of cellular processes of embryonic and adult tissues (1)(2)(3). Activin A and activin B are homodimers of inhibin ␤A and ␤B subunits, respectively, with established roles in the control of many cell types including those throughout the reproductive axis (1, 4 -6).…”

“…The two isoforms, FS315 and FS288, are differentially expressed in most tissues (19,20). The FS315 form is the predominant circulating form, whereas the shorter FS288 form lacking the C-terminal tail associates tightly with heparan sulfate chains of cell surface proteoglycans and is presumed to be the form that acts locally to modulate activin signaling (2,(21)(22)(23). This local function of follistatin is, in turn, controlled by the actions of activin.…”

Reconstitution and Analysis of Soluble Inhibin and Activin Receptor Complexes in a Cell-free System

“…Activins A and B, members of the transforming growth factor-␤ (TGF-␤) 1 superfamily of growth and differentiation factors, have a variety of actions in both embryonic and adult tissues, including tissue fate determination in vertebrate embryos, regulation of follicle-stimulating hormone biosynthesis in pituitary gonadotrophs, and regulation of gametogenesis in ovaries and testes (reviewed in Ref. 1).…”