Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis

Abstract

Spermatogenesis is a highly regulated process of germ cell proliferation and differentiation, starting from spermatogonia to spermatocytes and giving rise to spermatids, the future spermatozoa. In addition to endocrine regulation, testicular cell-cell interactions are essential for spermatogenesis. This precise control is mediated through paracrine/autocrine pathways, direct intercellular contacts and through intercellular communication channels, consisting of gap junctions and their constitutive proteins, the connexins. Gap junctions are localized between adjacent Leydig cells, between Sertoli cells and between Sertoli cells and specific germ cells. This review focuses on the distribution of connexins within the seminiferous epithelium, their participation in gap junction channel formation, the control of their expression and the physiological relevance of these junctions in both the Sertoli-Sertoli cell functional synchronization and the Sertoli-germ cell dialogue. In this review, we also discuss the potential implication of disrupted connexin in testis cancer, since impaired expression of connexin has been described as a typical feature of tumoral proliferation.

Figure 1.

Schematic representation of gap junction plaque, gap junction channel and connexins. Gap junctions are aqueous channels formed by the docking of two hemichannels (connexons) between two adjacent cells. Each hemi-channel is composed of six transmembrane proteins (connexins). Each connexin monomer is composed of four transmembrane domains with two extracellular loops, one intracellular loop and intracellular carboxyl and amino ends.

Figure 2.

Connexin 43 expression within the rat seminiferous epithelium. (a) Cx43 immunolabelling (red fluorescence) in Sertoli cells immunopositive for vimentin (green fluorescence), a specific marker of Sertoli cell within the seminiferous epithelium. Nuclei of the two adjacent Sertoli cells and germ cells are identified by DAPI staining (blue fluorescence). Merge indicates that Cx43 immunosignal is detected between Sertoli cells (arrow) and between Sertoli and germ cells (arrowhead). (b) Schematic three-dimensional representation of a seminiferous tubule with Sertoli cells (Sc) and germ cells (gc). The red curved lines represent gap junctions. (c) Isolated seminiferous tubules are observed in two different angles as described in the schematic representation. Side view (left panel, XY axis) and face view (right panel, XZ axis) show the basal organization of Sertoli cells determined by vimentin immunolabeling (green fluorescence) and the localization of Cx43 (red fluorescence). Note that Cx43 is present between Sertoli cells distributed along the XY axis and the XZ axis. Scale bars, (a) 5 µm; (c) 15 µm.

Figure 3.

Schematic illustration of events and effectors that control spermatogenesis. In the physiological situation, hormones, specific Cx association between compatible Cxs, and Cx interacting proteins control gap junction communication between Sertoli cells and between Sertoli and germ cells. In physiopathological conditions a rupture of this equilibrium (genetic, epigenetic, environmental influence) may be conducive either to hypofertility or abnormal tumor cell proliferation.