Regulation of blood-testis barrier dynamics: An in vivo study
Wong,Ching-hang; Mruk,Dolores D.; Lui,Wing-Yee; Cheng,Chuen-yan
Journal of Cell Science 117(5): 783-798
Publication date: 2004
An in vivo model was used to investigate the regulation of tightjunction (TJ) dynamics in the testis when adult rats were treatedwith CdCl. It was shown that the CdCl-induced disruption ofthe blood-testis barrier (BTB) associated with a transient inductionin testicular TGF-ß2 and TGF-ß3 (but notTGF-ß1) and the phosphorylated p38 mitogen activatedprotein (MAP) kinase, concomitant with a loss of occludin andzonula occludens-1 (ZO-1) from the BTB site in the seminiferousepithelium. These results suggest that BTB dynamics in vivoare regulated by TGF-ß2/-ß3 via the p38MAP kinase pathway. Indeed, SB202190, a specific p38 MAP kinaseinhibitor, blocked the CdCl-induced occludin and ZO-1 lossfrom the BTB. This result clearly illustrates that CdCl mediatesits BTB disruptive effects via the TGF-ß3/p38 MAPkinase signaling pathway. Besides, this CdCl-induced occludinand ZO-1 loss from the BTB also associated with a significantloss of the cadherin/catenin and the nectin/afadin protein complexesat the site of cell-cell actin-based adherens junctions (AJs).An induction of -macroglobulin (a non-specific protease inhibitor)was also observed during BTB damage and when the seminiferousepithelium was being depleted of germ cells. These data illustratethat a primary disruption of the BTB can lead to a secondaryloss of cell adhesion function at the site of AJs, concomitantwith an induction in protease inhibitor, which apparently isused to protect the epithelium from unwanted proteolysis. -Macroglobulinwas also shown to associate physically with TGF-ß3,afadin and nectin 3, but not occludin, E-cadherin or N-cadherin,indicating its possible role in junction restructuring in vivo.Additionally, the use of SB202190 to block the TGF-ß3/p-38MAP kinase pathway also prevented the CdCl-induced loss ofcadherin/catenin and nectin/afadin protein complexes from theAJ sites, yet it had no apparent effect on -macroglobulin.These results demonstrate for the first time that the TGF-ß3/p38MAP kinase signaling pathway is being used to regulate bothTJ and AJ dynamics in the testis, mediated by the effects ofTGF-ß3 on TJ- and AJ-integral membrane proteins andadaptors, but not protease inhibitors.