Connexin 43 a check-point component of cell proliferation implicated in a wide range of human testis diseases

Abstract

Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases.

Fig. 1

Schematization of testis section illustrating the seminiferous tubules composed by Sertoli cells and germ cells at different stages of development and the interstitium with Leydig cells

Fig. 2

Schematic architecture of gap junction plaque, gap junction channel, gap junction hemi-channel or connexon and connexin. Each intercellular channel or gap junction provides an axial channel that interconnects the cytoplasms of two adjacent cells (cell 1 and cell 2) and allow the direct exchange of molecules with a relative molecular mass up to 1 kDa. Hemi-channels or connexons are formed of six connexin subunits that exhibit four transmembranous domains (M1–M4), two extracellular loops (E1 and E2), and three cytoplasmic domains including one intracellular loop (IL) and cytoplasmic NH₂- and COOH-termini

Fig. 3

Schematic illustration of human testicular diseases associated with impairment of Cx43. In physiological situations, Sertoli cell Cx43 independently or dependently of gap junction channels participates in the control of germ cell proliferation, differentiation, survival, and apoptosis required for spermatogenesis. In physiopathological conditions, for example under the influence of genetic, epigenetic and/or environmental factors, a decreased or complete rupture of the control of germ cells by Sertoli cells through Cx43 can conduce either to hypospermatogenesis, which first leads to man hypofertility, or to abnormal tumor cell proliferation, which finally leads to testicular germ cell tumors