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 304

2008 ). Even though deletion of JAM-A in mice led to reduced litter size, this
is probably resulted from impaired motility of spermatozoa as JAM-A was also
shown to be involved in sperm tail formation ( Shao et al., 2008 ).
Unlike claudins and occludin whose functions are mostly related to the
TJ-permeability barrier as these are structural components of the blood-
tissue barriers, JAMs are involved in numerous cellular functions and patho-
logical conditions, such as leukocyte migration, angiogenesis, hypertension
and tumorigenesis ( Bazzoni, 2011 ). Among them, the participation of JAMs
in the transmigration of leukocyte across the endothelial TJ barrier during
inflammation is of great interest since preleptotene spermatocytes may be
utilizing JAMs to traverse the BTB with similar mechanism ( Wang and
Cheng, 2007 ). It is noted that besides Sertoli cells, germ cells also expressed
JAM proteins including JAM-A and JAM-C ( Wang and Cheng, 2007 ), thus
it was proposed that other than playing the role for anchoring germ cells to
Sertoli cells, JAMs may also be responsible for the spermatocyte transit at
the BTB. In fact, the loss of JAM-C, an integrated component of the apical
ES at the Sertoli-spermatid interface, led to failure of spermiogenesis and
infertility ( Gliki et al., 2004 ). In short, much work is needed to define the
role of JAMs during spermatogenesis, in particular, its function at the BTB.
2.1.4. ZO Adaptor Proteins
Underneath the TJs, cytoplasmic plaques are formed via the cytoplasmic tails
of TJ proteins directly associated with adaptor proteins, such as ZO proteins,
at a 1:1 stoichiometric ratio (e.g. occludin-ZO-1, claudin-ZO-1, JAM-
ZO-1), which in turn bind to the underlying actin filaments. As such, TJ
proteins are linked to actin cytoskeleton for the support of barrier integrity.
Three ZO proteins have been identified thus far and they are ZO-1, ZO-2
and ZO-3, which share sequence homology with each other and among
them, ZO-1 is the predominant adaptor protein ( Gonzalez-Mariscal et al.,
2000 ; Tsukita et al., 2009 ). ZO proteins belong to the membrane-associated
guanylate kinase (MAGUK) family, and beginning from their N-terminal
region, they all have three PDZ domains, to be followed by an SH3 domain,
a GUK domain and a cytoplasmic tail. The first PDZ domain was shown to
bind to claudins ( Itoh et al., 1999a ) while the second one is necessary for
homo- or heterodimerization between ZO proteins ( Utepbergenov et al.,
2006 ; Wittchen et al., 1999 ), and the third PDZ domain is needed for inter-
acting with JAMs ( Bazzoni et al., 2000 ; Ebnet et al., 2000 ). ZO proteins
associate with occludin using the GUK domain ( Furuse et al., 1994 ; Haskins
et al., 1998 ; Itoh et al., 1999b ), with actin filaments link to the ZO proteins