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Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling.
[hydrocephalus with stenosis of the aqueduct of sylvius]
Rho
family
guanosine
triphosphatase
(
GTPase
)
3
(
Rnd
3
)
,
a
member
of
the
small
Rho
GTPase
family
,
is
involved
in
the
regulation
of
cell
actin
cytoskeleton
dynamics
,
cell
migration
,
and
proliferation
through
the
Rho
kinase-dependent
signaling
pathway
.
We
report
a
role
of
Rnd
3
in
the
pathogenesis
of
hydrocephalus
disorder
.
Mice
with
Rnd
3
genetic
deletion
developed
severe
obstructive
hydrocephalus
with
enlargement
of
the
lateral
and
third
ventricles
,
but
not
of
the
fourth
ventricles
.
The
cerebral
aqueducts
in
Rnd
3
-
null
mice
were
partially
or
completely
blocked
by
the
overgrowth
of
ependymal
epithelia
.
We
examined
the
molecular
mechanism
contributing
to
this
Rnd
3
-
deficiency
-mediated
hydrocephalus
and
found
that
Rnd
3
is
a
regulator
of
Notch
signaling
.
Rnd
3
deficiency
,
through
either
gene
deletion
or
siRNA
knockdown
,
resulted
in
a
decrease
in
Notch
intracellular
domain
(
NICD
)
protein
degradation
.
However
,
there
was
no
correlated
change
in
mRNA
change
,
which
in
turn
led
to
an
increase
in
NICD
protein
levels
.
Immunoprecipitation
analysis
demonstrated
that
Rnd
3
and
NICD
physically
interacted
,
and
that
down-regulation
of
Rnd
3
attenuated
NICD
protein
ubiquitination
.
This
eventually
enhanced
Notch
signaling
activity
and
promoted
aberrant
growth
of
aqueduct
ependymal
cells
,
resulting
in
aqueduct
stenosis
and
the
development
of
congenital
hydrocephalus
.
Inhibition
of
Notch
activity
rescued
the
hydrocephalus
disorder
in
the
mutant
animals
.
Diseases
Validation
Diseases presenting
"cerebral aqueducts"
symptom
hydrocephalus with stenosis of the aqueduct of sylvius
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