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 296

In this review, we focus on the biology and regulation of the BTB, in par-
ticular, the involvement of the two mTOR signal complexes, namely mTOR
complex 1 (mTORC1) and mTOR complex 2 (mTORC2), in regulating
the intriguing dynamics of the BTB during the epithelial cycle. Studies on
mTOR have largely been focused on the role of mTOR as a key modulator
of cell survival, particularly in cancer biology ( Khokhar et al., 2011 ; Wander
et al., 2011 ), since mTOR plays a central role in regulating protein synthesis for
cell growth, cell proliferation and survival ( Howell and Manning, 2011 ; Sen-
qupta et al., 2010 ). However, recent studies have shown that mTOR also takes
part in a variety of cellular events including actin cytoskeleton reorganization,
aging, autophagy, immune responses and barrier function ( Inoki et al., 2011 ;
Mok et al., 2012a ; Mok et al., 2012c ; Oh and Jacinto, 2011 ; Vassiliadis et al.,
2011 ; Weichhart, 2012 ). Studies have shown that in podocytes, which are the
cells that establish the blood-urine barrier in the kidney, a disruption of the
mTOR signaling perturbs the barrier function as a result of internalization of
the TJ-adaptor protein ZO-1 ( Shorning et al., 2011 ) and reduced expression
of slit diaphragm proteins (proteins which are essential for cell-cell contact and
hence barrier function in podocytes) ( Vollenbroker et al., 2009 ). More impor-
tant, the involvement of mTOR in the BTB modulation via reorganization
of actin cytoskeleton has been demonstrated in studies using RNAi to silence
rpS6, a downstream signaling molecule of mTORC1 ( Meyuhas, 2008 ), since
its knockdown was found to promote TJ-barrier function ( Mok et al., 2012c ).
On the other hand, the knockdown of rictor, a binding partner of mTORC2
( Sarbassov et al., 2004 ), was shown to disrupt BTB function ( Mok et al., 2012a ),
illustrating the antagonistic effects of these two mTOR complexes on BTB
dynamics. In order to have a better understanding of how the BTB is regulated
by mTOR, we first provide an update on the latest status of research on the
different junction types and the constituent adhesion proteins at the BTB, and
how they interact with each other to maintain the barrier homeostasis.We then
provide a brief background on mTOR such as the components of the two
mTOR signaling complexes and their functions. Finally, we will examine some
recent findings regarding the “yin” and “yang” of mTORs on BTB dynamics
via the differential actions of mTORC1 and mTORC2 on BTB function.
2. ACTIN-BASED CELL JUNCTIONS AT BTB
Among all the blood-tissue barriers, such as the blood-brain barrier and
the blood-urine barrier which are created between neighboring endothelial
cells, cell junctions are typically arranged in whichTJs are localized at the apical