Physiological roles of connexins and pannexins in reproductive organs

Abstract

Reproductive organs are complex and well-structured tissues essential to perpetuate the species. In mammals, the male and female reproductive organs vary on their organization, morphology and function. Connectivity between cells in such tissues plays pivotal roles in organogenesis and tissue functions through the regulation of cellular proliferation, migration, differentiation and apoptosis. Connexins and pannexins can be seen as major regulators of these physiological processes. In the present review, we assembled several lines of evidence demonstrating that these two families of proteins are essential for male and female reproduction.

Fig. 1

Connexin and pannexin expression in the testis. The tables summarize the presence of the different Cx and Panx isoforms, which have been identified in the interstitial compartment (gray table), the seminiferous tubules (green table) and the germ cell lineage (blue table) of various species. The red rectangles represent gap junctions

Fig. 2

Schematic representation of connexin and pannexin expressions along the epididymis during aging. The top panel is a scheme of the localization of gap junctions and Panxs within the epididymis epithelium. The bottom panel is a graphical representation of Cx isoform expression related to age and epididymis position. Two distinct parts of the epididymis, namely the caput/corpus and the cauda, are represented on a gray tube. Maturation from young rodent epididymis to adult and mature epididymis is schematized by an arrow from top to bottom. Expression levels for each connexin isoform are represented by the blue column proportionally varying in thickness

Fig. 3

a Role of gap junctions in the ovarian follicle. Cx37 and Cx43 are the predominantly expressed Cxs in mammalian follicles. Cx43 forms gap junctions (yellow) between the cumulus cells. Granulosa cells are metabolically coupled with oocytes by transzonal projections from the granulosa cell traversing the zona pellucida (ZP) and forming gap junctions at the oocyte plasma membrane (red). Animal models revealed that Cx37 forms gap junctions at the granulose cell–oocyte interface, which are responsible for the exchange of metabolites and signaling molecules, such as cyclic guanosine monophosphate, important for folliculogenesis. b Induction of gap junctions during implantation. During the receptive phase after ovulation, Cx expression and GJIC are completely repressed in the endometrium by ovarian progesterone. Upon blastocyst attachment, Cx26 expression (yellow) is locally induced in the luminal epithelium and, shortly after Cx43 expression (red), is induced in underlying stromal cells corresponding with formation of the implantation chamber. Cx43 expression further increases through the stromal compartment (arrows), characterizing its transformation into a secretory active decidua. c Connexin expression during lineage formation in the early rodent embryo. With formation of the early lineages, the expression of Cxs becomes immediately restricted to specific lineages. Whereas Cx43 is found in gap junctions throughout the epiblasts, the extraembryonic endoderm expresses Cx26 and Cx32. The proliferating diploid cells of the early trophoblast lineage express Cx31 and Cx31.1, which play critical roles in regulating trophoblast stem cell differentiation and development of the placenta

Fig. 4

Comparative connexin expression in mouse and human placenta. Humans and rodents have a discoid shaped hemochorial placenta (b, e), where maternal blood has direct contact with fetal trophoblasts. In mice, invasive secondary trophoblast giant cells (TGCs) differentiate from the Cx31-expressing spongiotrophoblast (SpT) cells and erode maternal spiral arteries, ensuring continuous blood flow into the placenta. Cx31-expressing and Cx31.1-expressing glycogen cells invade into the decidua (a). In human placenta, Cx40-expressing cytotrophoblast (CytT) cells are the functional homologues of Cx31-expressing SpT cells. Here, Cx40-expressing cells, detaching from the columns, change from a proliferative to an invasive phenotype. Detached cells loose Cx40 expression and differentiate into TGCs or into endovascular EVT cells, which erodes maternal spiral arteries (d). The exchange of metabolites occurs over a continuous layer of syncytiotrophoblast (SynT) cells. In the mouse (c), mononucleated CytT cells fuse into two layers of SynT cells, which are coupled via large gap junction plaques, composed of Cx26 (yellow). In human placenta, CytT cells express Cx43 (red), which mediates the fusion to a single SynT cell layer (f)