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Conditional N-WASP knockout in mouse brain implicates actin cytoskeleton regulation in hydrocephalus pathology.
[wiskott-aldrich syndrome]
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
"hydrocephalus"
symptom
achondroplasia
alexander disease
canavan disease
congenital toxoplasmosis
harlequin ichthyosis
hirschsprung disease
homocystinuria without methylmalonic aciduria
hydrocephalus with stenosis of the aqueduct of sylvius
krabbe disease
monosomy 21
proteus syndrome
severe combined immunodeficiency
sneddon syndrome
von hippel-lindau disease
wiskott-aldrich syndrome
This symptom has already been validated