Abstract
Germ cells develop in a sophisticated immune privileged microenvironment provided by specialized junctions contiguous the basement membrane of the adjacent Sertoli cells that constituted the blood-testis barrier (BTB) in seminiferous epithelium of testis in mammals. Deciphering the molecular regulatory machinery of BTB activity is central to improve male fertility and the role of post-translational modification including SUMOylation pathway is one of the key factors. Herein, we unveiled the mystery of the SUMO-2/3 specific protease SENP3 (Sentrin-specific protease 3) in BTB dynamics regulation. SENP3 is predominantly expressed in the nucleus of Sertoli and spermatocyte cells in adult mouse testis, and knockdown of SENP3 compromises tight junction in Sertoli cells by destructing the permeability function with a concomitant decline in trans-epithelial electrical resistance in primary Sertoli cells, which could attribute to the conspicuous dysfunction of tight junction (TJ) proteins (e.g., ZO-1, occludin) at the cell-cell interface due to the inactivation of STAT3. Moreover, SENP3 knockdown disrupts F-actin architecture in Sertoli cells through intervening Rac1/CDC42-N-WASP-Arp2/3 signaling pathway and Profilin-1 abundance. Our study pinpoints SENP3 might be a novel determinant of multiple pathways governing BTB dynamics in testis to support germ cells development in mammals.
Highlights
Spermatogenesis is an inherently complicated intricate process that produce the male germ cells termed sperms and thereby holds the heart of male fertility
Our study for the first time deciphers the functional relevance of sentrin/SUMO-specific proteases 3 (SENP3) in blood-testis barrier (BTB) dynamic regulation by dictating tight junction (TJ) integrity and actin architecture in mouse Sertoli cells which defines SENP3 as a novel determinant in mammalian spermatogenesis program
Previous studies have shown that SUMO-1 and SUMO-2/3 participate in human spermatogenesis, and the high expression of SUMO-2 is observed in rat Sertoli cells [17, 36]
Summary
Spermatogenesis is an inherently complicated intricate process that produce the male germ cells termed sperms and thereby holds the heart of male fertility. BTB is anatomically constituted of tight junction (TJ) composing of co-existing basal ectoplasmic specializations www.impactjournals.com/oncotarget (basal ES), gap junction (GJ) and desmosome between adjacent Sertoli cells, which are near the basement membrane of seminiferous epithelium that partitions seminiferous epithelium into the basal and apical compartments [3]. The movement of preleptotene spermatocytes in immune privileged microenvironment without compromising its integrity in adult testes is supported by extensive restructuring of specialized junction between Sertoli-Sertoli cells [4]. BTB dynamics have been reported to be regulated by a spectrum of cytokines and testosterone which orchestrate actin architecture and the function of integral membrane proteins via MAPK signaling cascade [5, 6, 7, 8]. The mechanisms underlying the regulation of BTB permeability and its participating molecules remain largely elusive
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