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Genetic deletion of afadin causes hydrocephalus by destruction of adherens junctions in radial glial and ependymal cells in the midbrain.
[hydrocephalus with stenosis of the aqueduct of sylvius]
Adherens
junctions
(
AJs
)
play
a
role
in
mechanically
connecting
adjacent
cells
to
maintain
tissue
structure
,
particularly
in
epithelial
cells
.
The
major
cell-cell
adhesion
molecules
at
AJs
are
cadherins
and
nectins
.
Afadin
binds
to
both
nectins
and
α-catenin
and
recruits
the
cadherin-β-catenin
complex
to
the
nectin-based
cell-cell
adhesion
site
to
form
AJs
.
To
explore
the
role
of
afadin
in
radial
glial
and
ependymal
cells
in
the
brain
,
we
generated
mice
carrying
a
nestin
-
Cre-mediated
conditional
knockout
(
cKO
)
of
the
afadin
gene
.
Newborn
afadin-c
KO
mice
developed
hydrocephalus
and
died
neonatally
.
The
afadin-c
KO
brain
displayed
enlarged
lateral
ventricles
and
cerebral
aqueduct
,
resulting
from
stenosis
of
the
caudal
end
of
the
cerebral
aqueduct
and
obliteration
of
the
ventral
part
of
the
third
ventricle
.
Afadin
deficiency
further
caused
the
loss
of
ependymal
cells
from
the
ventricular
and
aqueductal
surfaces
.
During
development
,
radial
glial
cells
,
which
terminally
differentiate
into
ependymal
cells
,
scattered
from
the
ventricular
zone
and
were
replaced
by
neurons
that
eventually
covered
the
ventricular
and
aqueductal
surfaces
of
the
afadin-c
KO
midbrain
.
Moreover
,
the
denuded
ependymal
cells
were
only
occasionally
observed
in
the
third
ventricle
and
the
cerebral
aqueduct
of
the
afadin-c
KO
midbrain
.
Afadin
was
co
-
localized
with
nectin-
1
and
N-
cadherin
at
AJs
of
radial
glial
and
ependymal
cells
in
the
control
midbrain
,
but
these
proteins
were
not
concentrated
at
AJs
in
the
afadin-c
KO
midbrain
.
Thus
,
the
defects
in
the
afadin-c
KO
midbrain
most
likely
resulted
from
the
destruction
of
AJs
,
because
AJs
in
the
midbrain
were
already
established
before
afadin
was
genetically
deleted
.
These
results
indicate
that
afadin
is
essential
for
the
maintenance
of
AJs
in
radial
glial
and
ependymal
cells
in
the
midbrain
and
is
required
for
normal
morphogenesis
of
the
cerebral
aqueduct
and
ventral
third
ventricle
in
the
midbrain
.
Diseases
Validation
Diseases presenting
"nectin-based cell-cell adhesion site"
symptom
hydrocephalus with stenosis of the aqueduct of sylvius
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