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notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish.
[cadasil]
Mutations
in
the
human
NOTCH
3
gene
cause
CADASIL
syndrome
(
cerebral
autosomal
dominant
arteriopathy
with
subcortical
infarcts
and
leukoencephalopathy
)
.
CADASIL
is
an
inherited
small
vessel
disease
characterized
by
diverse
clinical
manifestations
including
vasculopathy
,
neurodegeneration
and
dementia
.
Here
we
report
two
mutations
in
the
zebrafish
notch
3
gene
,
one
identified
in
a
previous
screen
for
mutations
with
reduced
expression
of
myelin
basic
protein
(
mbp
)
and
another
caused
by
a
retroviral
insertion
.
Reduced
mbp
expression
in
notch
3
mutant
embryos
is
associated
with
fewer
oligodendrocyte
precursor
cells
(
OPCs
)
.
Despite
an
early
neurogenic
phenotype
,
mbp
expression
recovered
at
later
developmental
stages
and
some
notch
3
homozygous
mutants
survived
to
adulthood
.
These
mutants
,
as
well
as
adult
zebrafish
carrying
both
mutant
alleles
together
,
displayed
a
striking
stress-associated
accumulation
of
blood
in
the
head
and
fins
.
Histological
analysis
of
mutant
vessels
revealed
vasculopathy
,
including
:
an
enlargement
(
dilation
)
of
vessels
in
the
telencephalon
and
fin
,
disorganization
of
the
normal
stereotyped
arrangement
of
vessels
in
the
fin
,
and
an
apparent
loss
of
arterial
morphological
structure
.
Expression
of
hey
1
,
a
well-known
transcriptional
target
of
Notch
signaling
,
was
greatly
reduced
in
notch
3
mutant
fins
,
suggesting
that
Notch
3
acts
via
a
canonical
Notch
signaling
pathway
to
promote
normal
vessel
structure
.
Ultrastructural
analysis
confirmed
the
presence
of
dilated
vessels
in
notch
3
mutant
fins
and
revealed
that
the
vessel
walls
of
presumed
arteries
showed
signs
of
deterioration
.
Gaps
in
the
arterial
wall
and
the
presence
of
blood
cells
outside
of
vessels
in
mutants
indicated
that
compromised
vessel
structure
led
to
hemorrhage
.
In
notch
3
heterozygotes
,
we
found
elevated
expression
of
both
notch
3
itself
and
target
genes
,
indicating
that
specific
alterations
in
gene
expression
due
to
partial
loss
of
Notch
3
function
might
contribute
to
the
abnormalities
observed
in
heterozygous
larvae
and
adults
.
Our
analysis
of
zebrafish
notch
3
mutants
indicates
that
Notch
3
regulates
OPC
development
and
mbp
gene
expression
in
larvae
,
and
maintains
vascular
integrity
in
adults
.
Diseases
Validation
Diseases presenting
"fins"
symptom
cadasil
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