Cell Signaling During Primitive Hematopoiesis
441
erythrocytes than wild type embryos and
these erythrocytes fail to hemoglobinize.
At earlier stages, an increase in apop-
tosis is detected in hematopoietic cells.
These defects can also be mimicked in
whole embryo culture by Noggin (a BMP2,
4 antagonist) and primitive erythroid
development can be rescued in vitamin
A-deFcient embryo explants by the addi-
tion of BMP4, suggesting that BMP4 is
critical for erythroblast survival and differ-
entiation.
Additional evidence for the role of BMPs
in regulating primitive erythrocyte sur-
vival and differentiation has recently been
revealed by altering BMP signaling in
Xenopus
embryos. When BMP signaling
is blocked speciFcally in the ectoderm
of developing embryos, by overexpression
of RNA encoding a dominant-negative
BMP receptor, mesodermally derived ery-
throid progenitors undergo programmed
cell death and very few mature primi-
tive erythrocytes are detected in otherwise
normal embryos. Thus, BMP4 signaling
is required in ectodermal cells in order
to generate an essential survival factor
for the erythroid lineage. Upregulation
of BMP signaling in the ectoderm by
microinjection of RNA encoding a consti-
tutively active BMP receptor also reduces
the number of circulating primitive ery-
throcytes; however, apoptosis does not
appear to be responsible for this decrease.
Remarkably, a concomitant increase in
circulating macrophages is also observed.
As previously discussed, the
Xenopus
ven-
tral blood island does make a signiFcant
contribution to circulating macrophages
in embryos, suggestive of the presence
of either multilineage myelopoietic pro-
genitors or macrophage progenitors in
the ventral blood island. These results
raise the intriguing possibilities that BMP
signaling regulates lineage commitment
(i.e. the choice to become erythroid or
nonerythroid myeloid cells) or speciF-
cally regulates the development of the
myeloid lineage. Unfortunately, cell cul-
ture assays that are routinely used to assay
the potential of mammalian and avian
hematopoietic progenitors
in vitro
are not
technically feasible with amphibian tis-
sues. As discussed in greater detail in the
next section, BMPs appear to act indirectly
on the ventral blood island, most likely
via the production of secondary signals in
the ectoderm.
To summarize, numerous transcription
factors, cytokines, and signaling molecules
have been identiFed that have essential
functions in the development of primitive
erythroid cells (±ig. 2). ±irst, mesoderm is
ventralized through the actions of BMPs.
Next, mesoderm is speciFed to adopt a
primitive hematopoietic fate by processes
that are not currently understood, but may
be better elucidated once the genetic basis
of the
cloche
mutant phenotype is revealed.
The production of erythroid progenitors
requires the transcription factors
scl
and
lmo2
, whereas maintenance of progenitors
requires the transcription factor
gata2
.
Signaling molecules that regulate their
expression are presumed to exist, but
have not been identiFed. The decision to
commit to an erythroid fate is regulated
together by
gata1
and
fog1
,a
n
dl
a
t
e
r
roles for these and other transcription
factors in erythroid differentiation are
likely. Expression of
gata1
is regulated at
the transcriptional level by cytokines such
as BMP4. Cytokines such as BMP4 and
EPOh
a
v
ea
l
s
ob
e
ensh
ownt
op
l
a
yan
essential role in proliferation and survival.
Numerous zebraFsh mutants that block
erythroid progenitor commitment and that
also fail to maintain normal numbers
of circulating primitive erythrocytes have
been isolated. Determining which genes
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