Abstract
Emerging evidence has shown that cell-cell interactions between testicular cells, in particular at the Sertoli cell-cell and Sertoli-germ cell interface, are crucial to support spermatogenesis. The unique ultrastructures that support cell-cell interactions in the testis are the basal ES (ectoplasmic specialization) and the apical ES. The basal ES is found between adjacent Sertoli cells near the basement membrane that also constitute the blood-testis barrier (BTB). The apical ES is restrictively expressed at the Sertoli-spermatid contact site in the apical (adluminal) compartment of the seminiferous epithelium. These ultrastructures are present in both rodent and human testes, but the majority of studies found in the literature were done in rodent testes. As such, our discussion herein, unless otherwise specified, is focused on studies in testes of adult rats. Studies have shown that the testicular cell-cell interactions crucial to support spermatogenesis are mediated through distinctive signaling proteins and pathways, most notably involving FAK, Akt1/2 and Cdc42 GTPase. Thus, manipulation of some of these signaling proteins, such as FAK, through the use of phosphomimetic mutants for overexpression in Sertoli cell epithelium in vitro or in the testis in vivo, making FAK either constitutively active or inactive, we can modify the outcome of spermatogenesis. For instance, using the toxicant-induced Sertoli cell or testis injury in rats as study models, we can either block or rescue toxicant-induced infertility through overexpression of p-FAK-Y397 or p-FAK-Y407 (and their mutants), including the use of specific activator(s) of the involved signaling proteins against pAkt1/2. These findings thus illustrate that a potential therapeutic approach can be developed to manage toxicant-induced male reproductive dysfunction. In this review, we critically evaluate these recent findings, highlighting the direction for future investigations by bringing the laboratory-based research through a translation path to clinical investigations.
Highlights
Toxicants that were shown to exert their disruptive effects at the intercellular junctions in target organs, including cells and tissues, such as at the neuromuscular interface, between embryonic mesenchymal cells during development possibly to perturb intercellular communication, were first reported in the 1950s and 1980s [1–4]
We focus our discussion on the latest findings regarding the role of an emerging signaling protein and its downstream pathway(s) in mediating toxicant-induced Sertoli and testis injury based on studies in rodents and humans, namely the focal adhesion kinase (FAK) (Figure 1), the Akt1/2 (Figure 2) and the FAK/Cdc42-based signaling pathways (Figure 2)
Other studies have shown that the basal ES/blood-testis barrier (BTB) and the apical ES are highly sensitive to the environmental toxicant cadmium in the testis [61,73,74]. These findings seemingly suggest that the ES that supports spermatid and Sertoli cell adhesion in the seminiferous epithelium during spermatogenesis may be utilizing specific signaling proteins and/or cascades, perhaps different from other cell epithelia
Summary
Toxicants that were shown to exert their disruptive effects at the intercellular junctions in target organs, including cells and tissues, such as at the neuromuscular interface, between embryonic mesenchymal cells during development possibly to perturb intercellular communication, were first reported in the 1950s and 1980s [1–4]. Studies in recent years have reported the involvement of members of the mitogen-activated protein kinases (MAPKs), such as p38 MAPK and ERK1/2 and their activated isoforms, in mediating blood-testis barrier (BTB) function at the Sertoli cell-cell interface [28–32]. FAK and two of its activated/phosphorylated forms, p-FAK-Y397 and p-FAK-Y407, are robustly but restrictively expressed at the apical ES [52,53] and apical/basal ES [54], respectively, which are the testis-specific cell-cell anchoring junction type [35,55,56] (Figure 3) Critical evaluation of these data, and, in particular, findings from more recent reports, have shed new insights regarding the path that should be taken so that this information can be considerably expanded in future studies. Exfoliation of elongated spermatids and unwanted remodeling of the BTB take place simultaneously, causing defects in spermatogenesis that lead to male reproductive dysfunction
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