The structures that underlie normal reproductive function

Abstract

The mechanisms and physiology of reproductive function have fascinated scientists throughout time. Recent cellular and molecular level structural studies have provided unprecedented insights into reproductive systems and signaling networks. This 'cutting edge' editorial provides a recent example in each of these areas, namely, the anatomical integrity of the follicle, the molecular structure of activin with its binding partners and the molecular regulation of inhibin. These three examples of structure informing function help explain reproductive health and may provide solutions to reproductive disease.

Figure 1. Preservation of follicular architecture

(A) Normal, healthy follicles progress from immature follicles to mature, antrum-containing Graffian follicles. Follicular architecture is crucial to this maturation, as follicles cultured on two- dimensional petri dishes lose their structure (B). Granulosa cells adhere to the plastic surface and no longer support a healthy oocyte (*). The low quality oocyte unsuccessfully attempts to reconstruct the native follicular design and is therefore rarely competent for fertilization. (C) Follicles cultured in three-dimensional alginate beads maintain support of the oocyte by the granulosa cells and grow from pre-antral to mature, antrum-containing follicles. The edge of the alginate bead (arrow) demonstrates the spherical nature of this culture system. (D) A cross section of a follicle cultured in alginate further displays the overwhelming preservation of structure when comparing this system to in vivo matured follicles. Scale bar = 100μm. Abbreviations: IF (immature follicle), A (antrum), PD (petri dish), GC (granulosa cells).

Figure 2. Regulation of activin signaling is vital for proper follicle development

Activin is a flexible dimer (1) which signals in an autocrine fashion via type II and type I receptors (2). In pituitary cells, the signal is propagated intracellularly via SMADs 3 and 4, which, together with the transcription factor Pitx2, promote FSHβ synthesis (3). FSH is released from the pituitary, and interacts with FSH receptors expressed on ovarian granulosa cells (4). FSH stimulates inhibin α-subunit and follistatin expression. Activin is locally inhibited by follistatin (5), which embraces the ligand, sequestering it from receptor binding. Thus, local activin activity decreases, as ovarian inhibin becomes the dominant non-steroidal hormone produced by the follicle. Follicular activin promotes the production of inhibin, which is released into circulation, completing the endocrine loop to inhibit pituitary activin signaling (6). Inhibin levels are also controlled by the dynamic exchange of SF-1 and LRH-1 on the promoter of the inhibin α gene (7). SF-1 is primarily associated in the basal state, while LRH-1 levels vary dramatically, increasing for enhanced expression of inhibin α. The ability to correlate structure with function in the control of pituitary FSH and ovarian follicle development is an exciting advance in reproductive biology.