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Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis.
[holt-oram syndrome]
Holt-
Oram
syndrome
is
an
autosomal
dominant
heart
-
hand
syndrome
caused
by
mutations
in
the
TBX
5
gene
.
Overexpression
of
Tbx
5
in
the
chick
proepicardial
organ
impaired
coronary
blood
vessel
formation
.
However
,
the
potential
activity
of
Tbx
5
in
the
epicardium
itself
,
and
the
role
of
Tbx
5
in
mammalian
coronary
vasculogenesis
,
remains
largely
unknown
.
To
evaluate
the
consequences
of
altered
Tbx
5
gene
dosage
during
proepicardial
organ
and
epicardial
development
in
the
embryonic
chick
and
mouse
.
Retroviral-mediated
knockdown
or
upregulation
of
Tbx
5
expression
in
the
embryonic
chick
proepicardial
organ
and
proepicardial-
specific
deletion
of
Tbx
5
in
the
embryonic
mouse
(
Tbx
5
(
epi-
/
)
)
impaired
normal
proepicardial
organ
cell
development
,
inhibited
epicardial
and
coronary
blood
vessel
formation
,
and
altered
developmental
gene
expression
.
The
generation
of
epicardial-derived
cells
and
their
migration
into
the
myocardium
were
impaired
between
embryonic
day
(
E
)
13
.
5
to
15
.
5
in
mutant
hearts
because
of
delayed
epicardial
attachment
to
the
myocardium
and
subepicardial
accumulation
of
epicardial-derived
cells
.
This
caused
defective
coronary
vasculogenesis
associated
with
impaired
vascular
smooth
muscle
cell
recruitment
and
reduced
invasion
of
cardiac
fibroblasts
and
endothelial
cells
into
myocardium
.
In
contrast
to
wild-
type
hearts
that
exhibited
an
elaborate
ventricular
vascular
network
,
Tbx
5
(
epi-
/
-
)
hearts
displayed
a
marked
decrease
in
vascular
density
that
was
associated
with
myocardial
hypoxia
as
exemplified
by
hypoxia
inducible
factor
-
1
α
upregulation
and
increased
binding
of
hypoxyprobe-
1
.
Tbx
5
(
epi-
/
-
)
mice
with
such
myocardial
hypoxia
exhibited
reduced
exercise
capacity
when
compared
with
wild-
type
mice
.
Our
findings
support
a
conserved
Tbx
5
dose-dependent
requirement
for
both
proepicardial
and
epicardial
progenitor
cell
development
in
chick
and
in
mouse
coronary
vascular
formation
.