360
Cell Junctions, Structure, Function, and Regulation
conjunction with
β
-catenin. These fnd-
ings suggest that plakophilin-1 and -2,
much like
β
-catenin and p120, may play
dual roles in the cell: a structural role at
the desmosome and a transcriptional role
in the nucleus.
Desmoplakin (DP) is the protein that
plays the central role in linking the desmo-
somal cadherin complex to intermediate
flament networks. There are two closely
related isoForms oF DP resulting From
alternative splicing, DP1-322 kD and DP2-
259 kD. Both Forms are Found in all
tissues except in the heart where only
DP1 is located. DP is a dumbbell-shaped
molecule that possesses three domains,
an N-terminal globular domain, a coiled-
coiled rod domain, and a carboxyterminal
globular domain, and bind to interme-
diate flaments. DP is part oF a large
Family oF cytoskeletal linking proteins
termed the plakin Family oF cytolinkers.
The Founding members oF this Family in-
c
lud
eDP
,th
eh
em
id
e
smo
som
a
lp
ro
t
e
in
BPAG-1 (BP230) and plectin, a cytoskele-
tal cross-linking protein with a wide tissue
distribution
.ThisFami
lyoFproteinsisde-
fned by an amino-terminal plakin domain,
which appears to contain protein interac-
tion motiFs that target individual plakin
Family members to specifc subcellular
destinations. In the case oF DP, the N-
terminal region oF this protein has been
shown to bind to plakoglobin, plakophilin,
and Dsg/Dsc. The coiled-coiled rod do-
main oF DP is believed to be responsible For
dimerization (possibly multimerization).
The length oF this region is variable; DP-
1 contains 599 AAs more than DP-2. The
last region contains three globular plakin
domains that are responsible For binding
to intermediate flaments.
A
ss
h
ow
ni
i
g
.1
2
(
b
)
,D
Pp
l
a
y
sa
central role in the desmosome as it is
the primary protein that connects to the
intermediate flaments. Gene knockout
studies have reinForced the importance oF
DP to desmosome Function. Initial gene
knockout studies Found that loss oF DP
was lethal at day E5.5 to 6.5 due to a loss oF
DP in extra-embryonic tissue surrounding
th
eem
b
r
y
o
.Th
eFun
c
t
i
ono
Fth
ee
x
t
r
a
-
embryonic tissue was rescued using an
approach that allows the extra-embryonic
t
issuetohaveaw
i
ld
-
typegeno
type
,wh
i
le
the developing embryonic tissue contains
the DP knockout. This approach allowed
development until embryonic day 10. As
expected, deFects were Found in the heart
and the skin, organs known to require
strong
cell–cell
adhesion
to
maintain
tissue
integrity.
The
neuroepithelium,
Found in the head Folds and in the lining
oF the spinal cord, was also aFFected by
the loss oF DP. Prior to neural tube
closure there is normally an increase in
desmosomes Followed by a loss oF these
junctions once the neural tube is Formed.
In
DP
/
embryos, the
neural
tube
was collapsed and the neuroepithelium
was disorganized. Interestingly, the loss
oF DP did not aFFect diFFerentiation oF
the neuroepithelium but prevented the
stabilization and/or completion oF neural
tube Formation.
The DP knockout animal also displayed
Fewer capillaries than wild-type mice. In-
terestingly, endothelial cells do not contain
desmosomes. Instead, plakoglobin and DP
bind to VE-cadherin (cadherin-5) Forming
a structure called the
complexus adherens
junction
or
syndesmosome
.Th
i
sjun
c
t
i
on
has been observed in the microcircula-
tion
in vivo
, but does not appear to be
present in large-vessel endothelium. In
DP
/
embryos, only the capillaries ap-
peared to be disrupted, while the large
vessels appeared to develop normally. In
addition, the DP
/
phenotype resembles
the VE-cadherin phenotype (
/
); both
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