Germ Cell-Sertoli Cell Junction Signaling

The signaling between the junction of germ cells and Sertoli cells is of paramount importance for timely germ cell movement within the seminiferous epithelium. Germ cell and Sertoli cell interactions in the testis occur through specialized junctions at sites of cell-cell and cell-matrix contact. These junctions include cadherin-cadherin junctions, laminin -Itg-α6 and Itg-β1 and nectin junctions. The apical ectoplasmic specialization (ES) is constituted by three different protein complexes at the Sertoli cell side; cadherin/Ctnn, nectin2/afadin, and integrin/FAK, which interact correspondingly with cadherins, nectin2/3 and laminin-γ3 on the spermatid surface. The N- and E-cadherin of the Sertoli cells bind to different catenin members like Ctnn-α, Ctnn-β, Ctnn-γ and p120Ctn. These in turn activate the kinases like Fer and c-Src. This is followed by subsequent activation of IQGAP1, MTMR2, the adaptors like axin and Zyx, cytoskeletal regulators like WASP, fimbrin, Epn, α-Actn; and the adhesion molecule like ZO1. Activation of cell adhesion molecules leads to F-actin/myosin7A/tubulin cross-bridging, actin polymerization and cell adhesion.Within the germ cells nectin2/3 remains associated with afadin, ponsin, Ctnn-α, Ctnn-β and Ctnn-γ, whereas nectin2 on the sertoli cells binds with afadin, ponsin, Ctnn-α, ZO1 and α-actn. Nectin2/3 and nectin2 interaction functions as an important regulator of F-actin/T-actin/myosin7A/KEAP1/tubulin/Epn complexes to increase Actin polymerization and cross-bridging and in turn cell adhesion.Germ cell adhesion and migration is also dependant on release of testosterone and cytokines (TGF-β and TNF-α). The Laminin-γ3 on the germ cell surface binds with Itg-α6/Itg-β1 leading to actin reorganization and ES stabilization, which is controlled by testosterone. Laminin-γ3 and testosterone induced activation of integrins leads to the phosphorylation of FAK and enhanced binding of FAK with PI3K, c-Src and ILK. FAK binds to PI3K and subsequently recruits its catalytic subunit to the plasma membrane, where it phosphorylates PIP2, producing a second messenger, PIP3. The accumulated PIP3 activates Akt1, then activated via phosphorylation by PDK-1. Both c-Src and phosphorylated Akt1 activates PAK, which in turn activate ERK and LIMK. The Integrin-Rho-Rac activation is another vital route for PAK stimulation. ERK is also activated by FAK and Akt1. Upon activation these kinases, PAK and ERK bring about cofilin disintegration and actin filament stabilization. Integrins and FAK also associates and activates p130CAS, Pxn, Gsn and Vcl, which in turn activate fimbrin/α-Actn/epsin/F-actin/tubulin/KEAP1/myosin7A complexes to increase actin polymerization and cell adhesion.Cytokines like TGF-β 3 and TNF-α disrupts junction dynamics and help in the timely release of spermatids by promoting activation of p38, ERK and JNK pathways. TGF-Beta3 activates the Ras-MEK-ERK and MEKK-MKK-p38 pathways that lead to actin depolarization, apical ES disruption and blood-testes barrier disruption resulting in spermatid/germ cell migration. Similarly, TNF-α activates the CDC42/Rac-MKK-JNK pathway to inhibit F-Actin polymerization. The JNK cascade also limits proteolysis of actin and other cytoskeletal modulators by regulating the production of protease inhibitor, α-2M. It binds to the extracellular TGF-β 3 and TNF-α and inhibits subsequent ligand/receptor interaction.Germ cell-Sertoli cell interactions thus affect spermatogenesis at the molecular, cellular and biochemical levels