Regulation of Blood–Testis Barrier (BTB) Dynamics during Spermatogenesis via the “Yin” and “Yang” Effects of Mammalian Target of Rapamycin Complex 1 (mTORC1) and mTORC2 - International Review of Cell and Molecular Biology - page 314

GJs to actin cytoskeleton, which is important for proper localization of GJs
( Giepmans and Moolenaar, 1998 ; Laing et al., 2001 ; Toyofuku et al., 1998 ).
Besides mediating signaling between neighboring cells, GJs are also involved
in modulating the function of AJs and TJs ( Derangeon et al., 2009 ; Kojima
et al., 2007 ) includingTJ-barrier function at the BTB ( Li et al., 2009 ). Studies
have shown that in cultured Sertoli cells, a transient induction of Cx33 coin-
cides with a surge in the expression of N-cadherin ( Chung et al., 1999 ), and
blocking the trans -interaction of connexons with synthetic peptides leads to
mislocalization of N-cadherin ( Lee et al., 2006 ), illustrating the involvement
of GJs in the assembly and maintenance of AJs in the testis. Furthermore,
the requirement of GJs in inducing TJ assembly and its maintenance was
revealed in studies via overexpression of exogenous Cx32 in hepatocytes
isolated from Cx32-deficient mice that led to an induction of TJs in these
cells ( Kojima et al., 2002 ). Furthermore, a disruption of GJ-communication
in Caco-2 cells (human colonic epithelial cell line) resulted in TJ-barrier dis-
ruption ( Morita et al., 2004 ). These studies illustrate GJ proteins themselves
and/or GJ-mediated cell-cell communication is essential to the assembly
and/or maintenance of AJs and TJs. Thus, GJs are expected to be crucial
for BTB maintenance during spermatogenesis. In fact, spermatogenesis was
disrupted in mice with Sertoli cell-specific deletion of Cx43 ( Brehm et al.,
2007 ; Carette et al., 2010 ). In these Cx43 SC only KO mice, spermatogen-
esis was arrested in which spermatogonia failed to differentiate beyond type
A ( Carette et al., 2010 ). Furthermore, a knockdown of Cx43 in cultured
Sertoli cells with an established functional TJ-permeability barrier by RNAi
perturbed the “resealing” of a disrupted TJ barrier induced by either Ca 2+
depletion or treatment with bisphenol A ( Li et al., 2010 ). Such a loss of the
ability of the Sertoli cell to “reseal” the disrupted TJ barrier following Cx43
knockdown was shown to be mediated, at least in part, by changes in the
localization of AJ and TJ proteins at the BTB, rendering their BTB pro-
teins incapable of redistributing to their proper sites to “reseal” the disrupted
BTB ( Li et al., 2010 ). Moreover, in cultured Sertoli cells, the simultaneous
knockdown of both Cx43 and plakophilin-2 (PKP-2 a desmosomal adaptor
protein) was found to induce mislocalization of TJ proteins occludin and
ZO-1, as well as an increase in endocytosis of N-cadherin, thereby destabi-
lizing the TJ barrier ( Li et al., 2009 ). Thus, these findings are consistent with
studies in other epithelia that GJs are required for proper functioning of basal
ES and TJs at the BTB in the rat testis, possibly mediated by transmitting sig-
nals among different junction types to coordinate their functions to maintain
the BTB homeostasis during the epithelial cycle of spermatogenesis.