442
Cell Signaling During Primitive Hematopoiesis
are mutated in these lines will yield
insights into how erythroid commitment
and
survival
is
achieved,
as
well
as
how erythroid-specifc gene expression
is regulated.
3
Role of Cell–Cell Interactions in Primitive
Hematopoiesis
Cell–cell interactions are responsible For
regulating many embryonic developmen-
tal events. Secreted signaling molecules
produced by both hematopoietic and non-
hematopoietic cells play a critical role
in primitive hematopoiesis through eF-
Fects on specifcation, migration, survival,
diFFerentiation, and regulating primitive
and
defnitive
potential.
In
the
em-
bryo, morphogenetic movements result
in hematopoietic cells contacting diFFerent
cell types, and thus, many microenviron-
ments that potentially influence their de-
velopment. In this section, we will review
tissue–cell interactions that are known to
regulate primitive hematopoiesis.
3.1
Extraembryonic Endoderm
During gastrulation in the mouse and the
chick, prospective hematopoietic meso-
derm migrates into the extraembryonic
region, where it comes into direct con-
tact with the extraembryonic endoderm
(known in the mouse as
visceral endo-
derm
, or VE). Studies oF cultured mouse
ES cells and cultured early-mid gastrula
stage mouse embryos have revealed a role
For the VE in normal hematopoiesis. ±or
example, hematopoiesis is impaired in em-
bryoid bodies (ES cells that diFFerentiate
into structures that resemble mouse gas-
trulae) that are rendered VE-defcient by
a genetic mutation. Likewise, removal oF
the VE From mid-gastrula stage mouse
embryos results in their subsequent Fail-
ure to speciFy hematopoietic precursors.
Indian hedgehog (Ihh), a member oF the
Hh Family oF signaling molecules, is ex-
pressed in the VE and can substitute
Fo
rVEFun
c
t
ioninh
em
a
topo
i
e
t
i
cd
e
v
e
l
-
opment. Although Ihh is suFfcient to
substitute For the VE-derived signal, it
is not required since
Ihh
mutant em-
bryos do not display deFects in blood
development, possibly owing to genetic
redundancy. The eFFect oF Ihh on cul-
tured VE-defcient embryos depends on
BMP4 signaling, raising the possibility
that VE-derived Ihh Functions to main-
tain early BMP signaling, thereby allowing
appropriate hematopoietic specifcation to
occur. A similar requirement For a diF-
Fusible extraembryonic endoderm signal
in chick primitive erythropoiesis has also
been demonstrated, yet the identity oF
this signal is not known. The VE may
also play an additional role in directing
the migration oF hematopoietic precur-
sors since these cells are the source oF
vegf
mRNA. As described earlier, VEG±
and related ligands are required For the
migration oF prospective hematopoietic
cells to a site within the yolk sac that
is permissive For hematopoietic develop-
ment. These fndings demonstrate that
VE-derived signals are essential For the ini-
tiation oF primitive hematopoiesis, yet their
role appears to be short-lived. At the time
that morphologically distinct hematopoi-
etic cells can be detected in the mouse yolk
sac, isolated yolk sac hematopoietic meso-
derm (which includes hematopoietic cells
as well as endothelial cells and smooth
muscle cell precursors) can diFFerentiate
autonomously in culture without the need
For any exogenous Factors.
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