An intracellular trafficking pathway in the seminiferous epithelium regulating spermatogenesis: a biochemical and molecular perspective

Abstract

During spermatogenesis, fully developed spermatids (i.e., spermatozoa) at the luminal edge of the seminiferous epithelium undergo 'spermiation' at stage VIII of the seminiferous epithelial cycle. This is manifested by the disruption of the apical ectoplasmic specialization (apical ES) so that spermatozoa can enter the tubule lumen and to complete their maturation in the epididymis. At the same time, the blood-testis barrier (BTB) located near the basement membrane undergoes extensive restructuring to allow transit of preleptotene spermatocytes so that post-meiotic germ cells complete their development behind the BTB. While spermiation and BTB restructuring take place concurrently at opposite ends of the Sertoli cell epithelium, the biochemical mechanism(s) by which they are coordinated were not known until recently. Studies have shown that fragments of laminin chains are generated from the laminin/integrin protein complex at the apical ES via the action of MMP-2 (matrix metalloprotease-2) at spermiation. These peptides serve as the local autocrine factors to 'destabilize' the BTB. These laminin peptides also exert their effects on hemidesmosome which, in turn, further potentiates BTB restructuring. Thus, a novel apical ES-BTB-hemidesmosome regulatory loop is operating in the seminiferous epithelium to coordinate these two crucial cellular events of spermatogenesis. This functional loop is further assisted by the Par3/Par6-based polarity protein complex in coordination with cytokines and testosterone at the BTB. Herein, we provide a critical review based on the latest findings in the field regarding the regulation of these cellular events. These recent findings also open up a new window for investigators studying blood-tissue barriers.

p-FAK-Tyr397 regulates spermatid adhesion in the rat testis via its effects on F-actin organization at the ectoplasmic specialization

“…These supports are mediated via gap junctions and perhaps intercellular bridges at the Sertoli-germ cell interface, including spermatogonia, spermatocytes, and step 1-7 spermatids (20,32). Once step 8 spermatids appear at stage VIII of the epithelial cycle, a testis-specific AJ known as apical ES arises, which replaces desmosome and gap junction to become the only anchoring device, and it persists through step 19 spermatids, until it is degenerated to allow the release of sperm at spermiation (5,6,22). The apical ES is typified by the presence of an array of actin filament bundles that lie perpendicular to the Sertoli cell plasma membrane apposing the step 8 -19 spermatid plasma membrane and are sandwiched in between the cisternae of endoplasmic reticulum and the Sertoli cell plasma membrane, surrounding almost the entire head of spermatids that confers both adhesion and polarity to spermatids (6,32,35).…”

Regulation of blood–testis barrier dynamics by TGF-β3 is a Cdc42-dependent protein trafficking event

“…At stage VIII of the seminiferous epithelial cycle, the BTB undergoes extensive restructuring to allow the transit of preleptotene spermatocytes from the basal to the apical compartment. At the same time, preleptotene spermatocytes differentiate into leptotene and zygotene spermatocytes (3) so that meiosis and postmeiotic germ cell development can take place in the apical compartment behind the BTB (2). While the BTB undergoes this cyclic restructuring throughout spermatogenesis, the immunological barrier conferred by the BTB is maintained at all time to segregate the postmeiotic germ cell development from the host immune system to avoid the production of antibodies against germ cell-specific antigens that attack its own sperms.…”

“…While the BTB undergoes this cyclic restructuring throughout spermatogenesis, the immunological barrier conferred by the BTB is maintained at all time to segregate the postmeiotic germ cell development from the host immune system to avoid the production of antibodies against germ cell-specific antigens that attack its own sperms. Previous studies have shown that cytokines (e.g., TGF-β2 and TGF-β3) and testosterone are working in concert to facilitate the transit of spermatocytes at the BTB while maintaining the immunological barrier (2,4). For instance, testosterone maintains the immunological barrier by inducing de novo synthesis of junction proteins (e.g., claudins and occludin) (5-7) as well as transcytosis of proteins from other sites of the Sertoli cells to promote the assembly of "new" TJ fibrils behind a spermatocyte in transit (4).…”

“…cytokines | GTPases | protein endocytosis | seminiferous epithelial cycle | spermatogenesis I n mammalian testis, the seminiferous epithelium is segregated into the basal and apical compartments by the blood-testis barrier (BTB), which is created by coexisting tight junction (TJ), basal ectoplasmic specialization [ES, a testis-specific atypical adherens junction (AJ) type], and desmosome gap junctions between adjacent Sertoli cells near the basement membrane (1,2). At stage VIII of the seminiferous epithelial cycle, the BTB undergoes extensive restructuring to allow the transit of preleptotene spermatocytes from the basal to the apical compartment.…”

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

“…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.…”