444
Cell Signaling During Primitive Hematopoiesis
in erythroid progenitors is a result of
loss
of
endothelial
cells,
which
may
normally produce factors that support
gata1
expression. Interestingly, coculture
of yolk sac hematopoietic cells with an en-
dothelial cell line signiFcantly enhances
hematopoietic cell proliferation. Thus, en-
dothelial cells that are in close contact
with developing primitive hematopoietic
cells are excellent candidates for supply-
ing critical factors that support primitive
hematopoiesis.
3.4
Role of the Microenvironment in Regulating
Primitive and DeFnitive Potential
Numerous lines of evidence suggest that
the microenvironment determines the
primitive or deFnitive potential of HSCs
and progenitors. ±or instance, HSCs from
an adult mouse can be ‘‘reprogrammed’’
to produce primitive cells by aggregat-
ing them to mouse blastocysts that are
then allowed to develop normally
in utero
.
In the resulting chimeric embryos, the
HSCs (or cells derived from them) colo-
nize the yolk sac and produce erythrocytes
that express embryonic
globin
.In
Xenopus
,
heterotopic transplantation of the dorso-
lateral plate (which contains deFnitive
hematopoietic precursors) to the ventral
blood island region results in dorsolateral
plate-derived circulating primitive erythro-
cytes. Conversely, transplanting the ventral
blood island to the dorsolateral plate region
suppresses production of primitive ery-
throcytes by the ventral blood island. What
regionally determines primitive versus
deFnitive fate? Nearby tissues undoubt-
edly play a role through their production
of extracellular signaling molecules. By us-
ing organisms such as
Xenopus
and chick
that are experimentally amenable to tis-
sue transplantation studies, it should be
possible to identify the tissues that influ-
ence primitive and deFnitive commitment.
What regulates primitive versus deFnitive
fate intracellularly? It has recently been
shown that forced expression of
hoxb4
,a
homeodomain transcription factor, can re-
program primitive progenitors to produce
deFnitive hematopoietic cells. Moreover,
numerous
Hox
genes are expressed in
deFnitive but not primitive HSCs and pro-
genitors. Perhaps screens for secreted fac-
tors that either suppress or enhance
hoxb4
expression in hematopoietic cells may
identify factors that influence primitive
and deFnitive commitment, respectively.
At the very least, determining what genes
are regulated by
hoxb4
should provide
some insight into how deFnitive poten-
tial is achieved at the expense of primitive
potential.
4
Summary and Perspectives
Although primitive hematopoiesis is tran-
sient, it plays an important role in develop-
ment by providing the Frst erythrocytes
and leukocytes of the embryo. It re-
mains to be determined if the primitive
hematopoietic site contributes long-lasting
HSCs with deFnitive potential; however,
it is clear that at least in some species,
some deFnitive hematopoietic progeni-
tors originate there. Numerous genes,
including transcription factors, secreted
signaling molecules and signal transduc-
tion machinery have been shown to play
a crucial role in the development of the
primitive lineage through loss of func-
tion analysis in mouse, gain and loss of
function studies in
Xenopus
and chick,
and mutagenesis screens in zebraFsh. Un-
doubtedly, additional genes that regulate
many aspects of blood development will
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