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Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart.
[holt-oram syndrome]
Heart
formation
requires
a
highly
balanced
network
of
transcriptional
activation
of
genes
.
The
homeodomain
transcription
factor
,
Shox
2
,
is
essential
for
the
formation
of
the
sinoatrial
valves
and
for
the
development
of
the
pacemaking
system
.
The
elucidation
of
molecular
mechanisms
underlying
the
development
of
pacemaker
tissue
has
gained
clinical
interest
as
defects
in
its
patterning
can
be
related
to
atrial
arrhythmias
.
We
have
analyzed
putative
targets
of
Shox
2
and
identified
the
Bmp
4
gene
as
a
direct
target
.
Shox
2
interacts
directly
with
the
Bmp
4
promoter
in
chromatin
immunoprecipitation
assays
and
activates
transcription
in
luciferase-reporter
assays
.
In
addition
,
ectopic
expression
of
Shox
2
in
Xenopus
embryos
stimulates
transcription
of
the
Bmp
4
gene
,
and
silencing
of
Shox
2
in
cardiomyocytes
leads
to
a
reduction
in
the
expression
of
Bmp
4
.
In
Tbx
5
(
del
/
+
)
mice
,
a
model
for
Holt-
Oram
syndrome
,
and
Shox
2
(
-
/
-
)
mice
,
we
show
that
the
T
-
box
transcription
factor
Tbx
5
is
a
regulator
of
Shox
2
expression
in
the
inflow
tract
and
that
Bmp
4
is
regulated
by
Shox
2
in
this
compartment
of
the
embryonic
heart
.
In
addition
,
we
could
show
that
Tbx
5
acts
cooperatively
with
Nkx
2
.
5
to
regulate
the
expression
of
Shox
2
and
Bmp
4
.
This
work
establishes
a
link
between
Tbx
5
,
Shox
2
and
Bmp
4
in
the
pacemaker
region
of
the
developing
heart
and
thus
contributes
to
the
unraveling
of
the
intricate
interplay
between
the
heart
-
specific
transcriptional
machinery
and
developmental
signaling
pathways
.
Diseases
Validation
Diseases presenting
"atrial arrhythmias"
symptom
holt-oram syndrome
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