Sertoli Cell-Sertoli Cell Junction Signaling

The Blood-Testes Barrier (BTB) acts as a physical barrier between blood vessels and seminiferous tubules of the testes. This barrier is composed of tight junctions (TJs) and adherens junctions (AJs) between sertoli cells, which are supporting cells of the seminiferous tubules that nourish the spermatogonia. In the testis, tight junctions and adherens junctions are dynamically remodeled to allow the movement of post-meiotic germ cells across the seminiferous epithelium for the timely release of spermatids into the tubular lumen. Three main functions are ascribed to the BTB: 1) To create a specialized environment, 2) To regulate the passage of molecules, and 3) To serve as an immunological barrier. When the BTB is breached and sperm enters the bloodstream, an autoimmune response against the sperm is launched.Morphologically, tight junctions form a continuous circumferential seal above the basal lamina of the seminiferous tubules in the testis. The major proteins of BTB tight junctions include occludins, claudins and junctional adhesion molecules (JAM). Occludins directly interact with proteins such as ZO1, ZO2, ZO3, ZONAB and PALS2. Claudin clusters interact with ZO1, ZO2, spectrin/fodrin and PILT, whereas the main adhesion molecules near JAM clusters include ZO1, PILT, spectrin/fodrin and CGN. These binding associations activate cytoskeletal proteins such as α-actinin, fimbrin, epsin, tubulin and myosin7A that in turn activate F-actin polymerization to enhance cell adhesion between two neighbouring sertoli cells. Similarly, the adherens junctions between sertoli cells consist of nectin and E-cadherin adhesion molecules, which are linked to the actin cytoskeleton through their binding proteins and catenins, respectively.Junction dynamics is affected by cytokines such as TNF and TGFβ3. However, their signals are thought to be fine-tuned to allow regulation and remodeling of various junction types in the testes. TGFβ3 acts via the p38 MAPK, JNK and ERK signaling pathways, while TNF acts mostly via the JNK pathway. ERK1/2, p38 MAPK and JNK activation control changes in testicular junction dynamics, cell division and differentiation, apoptosis and cell migration. E-cadherin induced activation of MAGI-2/3 prevents degradation in sertoli cells. Such signaling creates a unique microenvironment for germ cell development around BTB and avoids passage of cytotoxic agents into the seminiferous tubules. Understanding the junction dynamics of the seminiferous epithelium may unfold new targets for non-hormonal male contraceptive development.