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Conditional N-WASP knockout in mouse brain implicates actin cytoskeleton regulation in hydrocephalus pathology.
[hydrocephalus with stenosis of the aqueduct of sylvius]
Cerebrospinal
fluid
(
CSF
)
is
produced
by
the
choroid
plexus
and
moved
by
multi-ciliated
ependymal
cells
through
the
ventricular
system
of
the
vertebrate
brain
.
Defects
in
the
ependymal
layer
functionality
are
a
common
cause
of
hydrocephalus
.
N-WASP
(
Neural-
Wiskott
Aldrich
Syndrome
Protein
)
is
a
brain
-enriched
regulator
of
actin
cytoskeleton
and
N-WASP
knockout
caused
embryonic
lethality
in
mice
with
neural
tube
and
cardiac
abnormalities
.
To
shed
light
on
the
role
of
N-WASP
in
mouse
brain
development
,
we
generated
N-WASP
conditional
knockout
mouse
model
N-WASP
(
fl
/
fl
)
;
Nestin-
Cre
(
NKO-Nes
)
.
NKO-Nes
mice
were
born
with
Mendelian
ratios
but
exhibited
reduced
growth
characteristics
compared
to
their
littermates
containing
functional
N-WASP
alleles
.
Importantly
,
all
NKO-Nes
mice
developed
cranial
deformities
due
to
excessive
CSF
accumulation
and
did
not
survive
past
weaning
.
Coronal
brain
sections
of
these
animals
revealed
dilated
lateral
ventricles
,
defects
in
ciliogenesis
,
loss
of
ependymal
layer
integrity
,
reduced
thickness
of
cerebral
cortex
and
aqueductal
stenosis
.
Immunostaining
for
N-
cadherin
suggests
that
ependymal
integrity
in
NKO-Nes
mice
is
lost
as
compared
to
normal
morphology
in
the
wild-
type
controls
.
Moreover
,
scanning
electron
microscopy
and
immunofluorescence
analyses
of
coronal
brain
sections
with
anti-acetylated
tubulin
antibodies
revealed
the
absence
of
cilia
in
ventricular
walls
of
NKO-Nes
mice
indicative
of
ciliogenesis
defects
.
N-WASP
deficiency
does
not
lead
to
altered
expression
of
N-WASP
regulatory
proteins
,
Fyn
and
Cdc
42
,
which
have
been
previously
implicated
in
hydrocephalus
pathology
.
Taken
together
,
our
results
suggest
that
N-WASP
plays
a
critical
role
in
normal
brain
development
and
implicate
actin
cytoskeleton
regulation
as
a
vulnerable
axis
frequently
deregulated
in
hydrocephalus
.
Diseases
Validation
Diseases presenting
"cardiac abnormalities"
symptom
22q11.2 deletion syndrome
holt-oram syndrome
hydrocephalus with stenosis of the aqueduct of sylvius
inclusion body myositis
kabuki syndrome
monosomy 21
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
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