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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
"neurodegeneration"
symptom
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
classical phenylketonuria
fabry disease
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
krabbe disease
neonatal adrenoleukodystrophy
neuralgic amyotrophy
oculocutaneous albinism
pyruvate dehydrogenase deficiency
triple a syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated