Tight junctions in the testis: new perspectives

Abstract

In the testis, tight junctions (TJs) are found between adjacent Sertoli cells at the level of the blood-testis barrier (BTB) where they coexist with basal ectoplasmic specializations and desmosome-gap junctions. The BTB physically divides the seminiferous epithelium into two distinct compartments: a basal compartment where spermatogonia and early spermatocytes are found, and an adluminal compartment where more developed germ cells are sequestered from the systemic circulation. In order for germ cells (i.e. preleptotene spermatocytes) to enter the adluminal compartment, they must cross the BTB, a cellular event requiring the participation of several molecules and signalling pathways. Still, it is not completely understood how preleptotene spermatocytes traverse the BTB at stage VIII of the seminiferous epithelial cycle. In this review, we discuss largely how TJ proteins are exploited by viruses and cancer cells to cross endothelial and epithelial cells. We also discuss how this information may apply to future studies investigating the movement of preleptotene spermatocytes across the BTB.

Figure 1.

A model describing the movement of preleptotene spermatocytes across the BTB. (a) An electron micrograph showing part of the seminiferous epithelium from the adult rat testis. Depicted here are two adjacent Sertoli cells resting on the tunica propria which is composed of the basement membrane (bm), a layer of peritubular myoid cells (pmc) and the lymphatic endothelium (see asterisks). The BTB is typified by coexisting junctions, namely TJs, basal ES and D-GJs. Red arrowheads point to bundles of actin microfilaments sandwiched in between the Sertoli cell plasma membrane and the endoplasmic reticulum (er), and these are characteristic of the basal ES. (b) A schematic view of a cross section of the seminiferous epithelium at stage VII of the seminiferous epithelial cycle, showing germ cells (i.e. spermatogonium, preleptotene spermatocyte, pachytene spermatocyte, elongating spermatid and elongated spermatid) at different stages of development. The BTB, which is situated above a migrating preleptotene spermatocyte (see circles), divides the seminiferous epithelium into two compartments: a basal compartment and an adluminal compartment. Sertoli (SC), peritubular myoid and Leydig cells are also depicted. (c) A magnified view of the BTB at stage VII of the seminiferous epithelial cycle before a preleptotene spermatocyte transits across the BTB. Different proteins (see key) that constitute the BTB are shown, and these include TJ, basal ES and D-GJ proteins, some of which are phosphorylated. Testosterone synthesized by Leydig cells can upregulate several BTB constituent proteins. Thus, it plays an important role in maintaining barrier function. Desmosome junctions are linked to intermediate filaments through an adaptor such as desmoplakin but as it is not yet known if this protein localizes to the BTB, it is depicted as a dotted line open circle with question mark. As described in the text for viruses and cancer cells, TJ proteins may regulate germ cell cycle progression. (d) A schematic view of a cross section of the seminiferous epithelium at late stage VIII of the seminiferous epithelial cycle immediately following spermiation. Shown here is a leptotene spermatocyte within the intermediate compartment. (e) A magnified view of the intermediate compartment at late stage VIII of the seminiferous epithelial cycle. During the movement of preleptotene spermatocytes across the BTB, the following cellular events are likely to take place. De novo protein synthesis, as well as testosterone, are likely to facilitate the assembly of a ‘new’ Sertoli cell barrier below a migrating preleptotene spermatocyte. Protein phosphorylation may also play a critical role in this cellular event. Cytokines released by Sertoli and germ cells regulate BTB constituent proteins by activating proteases, which cleave proteins and/or by initiating endocytosis, which internalizes integral membrane proteins. Endocytosed integral membrane proteins may undergo proteolysis, and soluble fragments of proteins may be produced by ectodomain shedding. These soluble fragments may have functions that are different from their full-length counterparts. Nevertheless, in both cases, the ‘old’ BTB situated above a leptotene spermatocyte is breached, signalling to preleptotene spermatocytes that they may begin to cross the barrier. Concurrently, proteins that have been endocytosed but not destined for proteolysis may travel to the opposite pole of the leptotene spermatocyte by transcytosis as barrier integrity must be maintained during spermatogenesis. Recycling of endocytosed proteins is probably facilitated by Rab GTPases and other proteins of the endocytic pathway. Before arriving at their final destination (i.e. below a leptotene spermatocyte), it is also possible that endocytosed proteins are transiently inserted back into the Sertoli cell plasma membrane to form homotypic or heterotypic interactions with the migrating germ cell, thereby creating a ‘channel.’ These events contribute to assembly of a ‘new’ BTB.