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 338

pathway, which is inhibited by PKB, was not activated and the level of
MMP-9 remained unchanged ( Mok et al., 2012a ). As discussed in Sec-
tion 3.2.1 , mTORC2 signaling complex regulates actin cytoskeleton via
PKC-α in multiple epithelia; thus, the knockdown of rictor by RNAi trig-
gered actin reorganization, and actin filaments were rearranged in Sertoli
cells with reduced F-actin to support the TJ-barrier function at the Sertoli
cell-cell interface ( Mok et al., 2012a ). Interestingly, following the rictor
knockdown in Sertoli cells by RNAi that led to a reduction in phosphory-
lated PKC-α, the expression of Cx26 and Cx43 in these Sertoli cells was
also downregulated ( Mok et al., 2012a ). Furthermore, TJ proteins occludin
and ZO-1 were also redistributed from the cell-cell interface and moved
into the cell cytosol ( Mok et al., 2012a ), thereby destabilizing cell adhe-
sion, leading to the Sertoli cell TJ-barrier disruption. These findings thus
illustrate that a knockdown of rictor in Sertoli cells leads to restructuring of
actin cytoskeleton, reducing cortical F-actin, this thus facilitates internaliza-
tion of TJ proteins and hence weakening the TJ barrier. More important,
it was demonstrated that a knockdown of rictor led to a disruption of GJ
communication between adjacent Sertoli cells based on a functional GJ-
channel assay ( Mok et al., 2012a ). Collectively, these findings thus support
the notion that during the seminiferous epithelial cycle of spermatogenesis,
rictor and, hence, mTORC2 signaling is essential for maintaining BTB
integrity. When rictor is downregulated during the epithelial cycle, such
as at stage VIII at the time of BTB restructuring, this leads to PKC-
α-mediated actin cytoskeleton reorganization that promotes endocytosis of
TJ proteins to destabilize the BTB above the preleptotene spermatocytes in
transient at the BTB. This process is also assisted by a downregulation of GJ
proteins, which coordinates with the timely “disassembly” of TJ and basal
ES at the site to facilitate the transit of spermatocytes.
4.4. A Hypothetic Model Based on The Antagonistic Effects
of mTORC1 and mTORC2 on BTB Function to Regulate its
Integrity during The Epithelial Cycle of Spermatogenesis
Based on recent findings as discussed above, it is clear that the action of
mTORC1 is to promote the “disassembly” of the BTB while mTORC2
supports BTB integrity. It is very likely that the simultaneous presence of
these two signaling complexes in the seminiferous epithelium that exert their
antagonistic effects on the underlying actin cytoskeleton at the BTB that
leads to changes in the localization of TJ proteins play a critical role in main-
taining the BTB integrity during the transit of preleptotene spermatocytes,