A local autocrine axis in the testes that regulates spermatogenesis

Abstract

Spermiation—the release of mature spermatozoa from Sertoli cells into the seminiferous tubule lumen—occurs by the disruption of an anchoring device known as the apical ectoplasmic specialization (apical ES). At the same time, the blood–testis barrier (BTB) undergoes extensive restructuring to facilitate the transit of preleptotene spermatocytes. While these two cellular events take place at opposite ends of the Sertoli cell epithelium, the events are in fact tightly coordinated, as any disruption in either process will lead to infertility. A local regulatory axis exists between the apical ES and the BTB in which biologically active laminin fragments produced at the apical ES by the action of matrix metalloproteinase 2 can regulate BTB restructuring directly or indirectly via the hemidesmosome. Equally important, polarity proteins play a crucial part in coordinating cellular events within this apical ES–BTB–hemidesmosome axis. Additionally, testosterone and cytokines work in concert to facilitate BTB restructuring, which enables the transit of spermatocytes while maintaining immunological barrier function. Herein, we will discuss this important autocrine-based cellular axis that parallels the hormonal-based hypothalamic–pituitary–testicular axis that regulates spermatogenesis. This local regulatory axis is the emerging target for male contraception.

Microbiota and the control of blood-tissue barriers

“…25 This structural disassembly and reassembly of the TJPs occurs at stage VIII in the rat and is tightly regulated by testosterone and cytokines. [27][28][29] Comparison of the BBB and BTB…”

Breast cancer resistance protein (Bcrp) and the testis—an unexpected turn of events

“…In fact, recent studies have shown that steroids, such as oestradiol-17b, testosterone and progesterone, can inhibit the transport activity of Bcrp and upregulate Bcrp expression and its cellular localisation in cancer cells, endothelial cells of the brain and endocrine organs. 21,41,42 Steroids, particularly testosterone and oestrogens, are known to regulate BTB and testicular Bcrp and spermatogenesis XJ Qian et al 456 function, [43][44][45][46] and Bcrp plays a significant role in regulating the transport of steroids across the myoid cells and Sertoli cells at the apical ES (Table 1). Additionally, the activity, expression and cellular distribution of Bcrp are regulated by steroids.…”

“…33 It is noted that the apical ES is an F-actin-rich testis-specific adherens junction, in which bundles of actin filaments that lie perpendicular to the plasma membrane of the Sertoli cell are sandwiched between cisternae of endoplasmic reticulum and the apposing Sertoli-spermatid plasma membrane. 14,46,56 Once the apical ES appears in step 8 spermatids during spermiogenesis, it is the only anchoring device, replacing desmosomes and gap junctions. It persists until step 19 spermatids when mature spermatozoa are released into the tubule lumen at spermiation.…”

“…It persists until step 19 spermatids when mature spermatozoa are released into the tubule lumen at spermiation. 46,56,57 Thus, the identification of Bcrp and its association with Eps8 and Arp3 suggest that Bcrp is involved in regulating F-actin organisation, converting actin filaments from their bundled configuration to a branched network, thereby destabilizing the apical ES adhesion function. 54,55 This phenomenon seems to suggest that Bcrp may be involved in other yet-to-be defined functions during spermatogenesis.…”

“…Furthermore, the concave side of the spermatid heads in stage VII tubules was recently shown to be the site where extensive endocytic vesicle-mediated protein trafficking occurs, [58][59][60] so that 'old' apical ES proteins (e.g., b1-integrin, nectin-3, laminin-a3, -b3 and -c3 chains) can be endocytosed and recycled to the newly arisen apical ES in step 8 spermatids during spermiogenesis at stage VIII of the epithelial cycle. 46,61 Nonetheless, the finding that Bcrp is expressed stage specifically by late spermatids in the adluminal compartment 33 has shown that this efflux drug pump may be used by late-stage spermatids to safeguard their development by pumping out unwanted substances in the adluminal compartment prior to their transformation to mature spermatozoa. This possibility must be carefully evaluated in future studies.…”