Biology Reference
In-Depth Information
via their cytoplasmic tails (
Fanning et al., 1998
;
Itoh et al., 1997
). The knock-
out of ZO-1 or ZO-2 in mice results in embryonic lethality (
Katsuno et al.,
2008
;
Xu et al., 2008
). This demonstrates these two ZO proteins are essential
for development, but little information can be deduced for their physiologi-
cal function from these knockout mice. The importance of ZO proteins in
recruitment of TJ proteins, especially claudins for the formation of TJs, was
revealed by cultured epithelial cell line without endogenous ZO-3, whereas
ZO-1 was knockout by homologous recombination, and ZO-2 was knock-
down by RNAi (
Umeda et al., 2006
). Interestingly, when ZO truncated
proteins containing only the N-terminus which has the three PDZ domains
were forcibly localized to lateral membrane and dimerized, TJs formed by
claudins were found to be distributed throughout the lateral membrane
(
Umeda et al., 2006
). This is in sharp contrast to the TJs formed by over-
expressing full length ZO-1 and ZO-2 as these TJs are precisely localized
to the apical junctional complex. These observations thus illustrate that the
interaction of SH3 domain and GUK domain in ZO proteins with AJs is
necessary for directing TJ proteins to their correct cellular location (
Umeda
et al., 2006
). The importance of ZO proteins in spermatogenesis was dem-
onstrated in a study by injecting ZO-2
−/−
embryonic stem cells into wild-
type blastocysts to generate viable ZO-2-deficient mice, these mice were
found to have reduced fertility, resulting from impaired spermatogenesis,
because the BTB was disrupted due to mislocalization of integral membrane
proteins claudin 11 and Cx43 at the site (
Xu et al., 2009
).
These studies thus illustrate the significance of ZO-adaptor proteins in
maintaining the TJ-barrier integrity by proper localization of TJ (and also
GJ) integral membrane proteins, and this is mediated by their connection
to the underlying actin filaments. This is particularly important for the BTB
where an extensive F-actin network is present, and is under cyclic restruc-
turing during the epithelial cycle of spermatogenesis. The maintenance and
modulation of barrier function by actin reorganization is demonstrated in
numerous studies. For instance, when actin depolymerization was induced
by latrunculin A (Lat A, a toxin produced by red sea sponge) in MDCK
cells, a disruption of the TJ barrier was detected, which was attributed to
the internalization of occludin that caused by the loss of the apical peri-
junctional F-actin ring underneath the TJs, illustrating the importance of
actin cytoskeleton for proper TJ-protein localization (
Shen and Turner, 2005
).
In a study using rat alveolar epithelial cells, strengthening of cortical actin
filaments induced by treatment of keratinocyte growth factor (KGF) led to
a tightening of the TJ barrier (
LaFemina et al., 2010
). The necessity of an
Search WWH ::
Custom Search