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First published online 20 January 2004
doi: 10.1242/jcs.00900

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Regulation of blood-testis barrier dynamics: an in vivo study

Population Council, Center for Biomedical Research, 1230 York Avenue, New York, NY 10021, USA

^* Author for correspondence (e-mail: y-cheng{at}popcbr.rockefeller.edu)

Accepted 22 September 2003

An in vivo model was used to investigate the regulation of tight junction (TJ) dynamics in the testis when adult rats were treated with CdCl₂. It was shown that the CdCl₂-induced disruption of the blood-testis barrier (BTB) associated with a transient induction in testicular TGF-ß2 and TGF-ß3 (but not TGF-ß1) and the phosphorylated p38 mitogen activated protein (MAP) kinase, concomitant with a loss of occludin and zonula occludens-1 (ZO-1) from the BTB site in the seminiferous epithelium. These results suggest that BTB dynamics in vivo are regulated by TGF-ß2/-ß3 via the p38 MAP kinase pathway. Indeed, SB202190, a specific p38 MAP kinase inhibitor, blocked the CdCl₂-induced occludin and ZO-1 loss from the BTB. This result clearly illustrates that CdCl₂ mediates its BTB disruptive effects via the TGF-ß3/p38 MAP kinase signaling pathway. Besides, this CdCl₂-induced occludin and ZO-1 loss from the BTB also associated with a significant loss of the cadherin/catenin and the nectin/afadin protein complexes at the site of cell-cell actin-based adherens junctions (AJs). An induction of ₂-macroglobulin (a non-specific protease inhibitor) was also observed during BTB damage and when the seminiferous epithelium was being depleted of germ cells. These data illustrate that a primary disruption of the BTB can lead to a secondary loss of cell adhesion function at the site of AJs, concomitant with an induction in protease inhibitor, which apparently is used to protect the epithelium from unwanted proteolysis. ₂-Macroglobulin was 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-38 MAP kinase pathway also prevented the CdCl₂-induced loss of cadherin/catenin and nectin/afadin protein complexes from the AJ sites, yet it had no apparent effect on ₂-macroglobulin. These results demonstrate for the first time that the TGF-ß3/p38 MAP kinase signaling pathway is being used to regulate both TJ and AJ dynamics in the testis, mediated by the effects of TGF-ß3 on TJ- and AJ-integral membrane proteins and adaptors, but not protease inhibitors.

Key words: Blood-testis barrier, Tight junctions, Adherens junctions, TGF-ß3, ₂-Macroglobulin, p38 MAP kinase

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