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 298

needs, such as development, cell migration and cell/tissue homeostasis ( Steed
et al., 2010 ; Tsukita et al., 2001 ). This flexibility of TJ is particularly important
for the BTB, which undergoes cyclic restructuring to facilitate the transit of
preleptotene spermatocytes while its integrity must be maintained to ensure
proper development of spermatids via spermiogenesis behind the barrier.
Furthermore, TJs are connected to actin cytoskeleton via adaptor proteins,
which include zonula occludens-1, -2 and -3 (ZO-1, -2, -3). To date, many
TJ proteins have been identified at the BTB, which include claudins, occlu-
din, junctional adhesion molecules ( JAMs), tricellulin and coxsackievirus and
adenovirus receptor (CAR) ( Cheng and Mruk, 2010b ; Steed et al., 2010 ;
Tsukita et al., 2001 ). Among these, claudins, occludin and JAMs are the best-
studied TJ proteins at the BTB, which are briefly reviewed herein.
2.1.1. Claudins
Claudins are a family of TJ proteins, each has four transmembrane domains,
two extracellular loops and a short cytoplasmic tail ( Elkouby-Naor and Ben-
Yosef, 2010 ). To date, 24 members of claudins have been identified ( Elkouby-
Naor and Ben-Yosef, 2010 ). Among these, claudin-1 through -8 and -11 have
been identified by northerns in rodent testes ( Furuse et al., 1998 ; Morita et al.,
1999a , 1999b ), whereas claudin 10, 12, and 23 were detected by microarray
analysis using mRNAs from rodent testes ( Singh et al., 2009 ). It is generally
accepted that claudins are the backbone of TJ strands and are responsible for
recruiting other TJ proteins, such as occludin to TJs. Forced expression of
exogenous claudins in fibroblasts was able to induce cell adhesion activity by
forming networks of TJ-strand-like ultrastructure at cell-cell contacts ( Furuse
et al., 1998 ; Kubota et al., 1999 ). Besides, the importance of claudins as the
core structural component of TJs is demonstrated by the inability of forming
an intact barrier in mice with specific claudin knockout. For example, mice
lacking claudin 1 died shortly after birth due to dehydration as a result of fail-
ure in epidermal barrier function ( Furuse et al., 2002 ). Deletion of claudin 5
in mice led to neonatal death, within 10 h after birth because of the absence
of the blood-brain barrier ( Nitta et al., 2003 ). Furthermore, knockout of
claudin 18 in mice led to disruption of permeability barrier of gastric epi-
thelia, causing paracellular H + leakage that results in atrophic gastric epithelia
( Hayashi et al., 2012 ). Knockout of claudin-11, which is expressed specifically
in oligodendrocytes and Sertoli cells, led to infertility in mice due to the lack
of BTB without TJ strands formed between Sertoli cells ( Gow et al., 1999 ).
Besides being the essential building block of TJs, claudins also determine the
properties of TJ barriers by assembling TJs with different claudin members.