Cell Signaling During Primitive Hematopoiesis
439
has been replaced with a version of
gata1
that contains a single amino acid change
that prevents binding to
fog1
, arrest at the
same stage of development as
gata1
/
embryos, suggesting that interactions be-
tween Gata1 and Fog1 are a requisite for
normal primitive erythroid development.
Numerous erythroid cell line studies have
also shown that
scl
regulates de±nitive ery-
thropoiesis through dynamic association
with other transcription factors, including
the formation of DNA binding complexes
containing Lmo2 and Gata1. The recent
creation of an adult hematopoietic-speci±c
knockout of
scl in vivo
demonstrates an
absolute requirement for
scl
in adult de±ni-
tive erythroid lineage development. Per-
sistent
scl
expression in erythroid progeni-
tors and circulating primitive erythroblasts
suggests that
scl
plays a similar role in
primitive erythrocyte differentiation.
A number of zebra±sh mutants that lack,
or have a severely reduced number of circu-
lating primitive erythroid cells have been
identi±ed. Among these mutants,
blood-
less
and
cloche
appear to affect progenitor
survival or expansion. The
bloodless
muta-
tion acts as a noncell autonomously since
wild type cells transplanted into
bloodless
mutant embryos cannot undergo primitive
hematopoiesis. This raises the possibility
that
bloodless
regulates or encodes a cy-
tokine. In
bloodless
mutants, the onset of
scl
expression is detected at the appropri-
ate time and place in the hematopoietic
mesoderm; however, only a few cells con-
tinue to express
scl
in the intermediate
cell mass and apoptosis is detected at later
stages. These data suggest that although
hematopoietic cells are speci±ed, they can-
not survive. The
cloche
mutation may
also regulate progenitor expansion. Trans-
planted
cloche
mutant cells in wild type
embryo hosts can occasionally contribute
to the primitive erythroid lineage, but far
less ef±ciently than similarly transplanted
wild type cells, suggestive of a defect in ery-
throid progenitor proliferation. Identifying
the genes encoded by
bloodless
and
cloche
will greatly enhance our understanding of
how progenitors are maintained.
A second zebra±sh mutant,
moonshine
,
fails to undergo erythroid progenitor com-
mitment. In
moonshine
mutants,
gata2
expression appears normal in hematopoi-
etic mesoderm, indicating that uncommit-
ted hematopoietic progenitors are present.
However,
gata1
expression is absent sug-
gesting that committed erythroid progen-
itors do not develop in the absence of
the
moonshine
gene. The gene encoded
by
moonshine
has not yet been reported,
and its characterization will undoubtedly
provide insights into how hematopoietic
gene expression is regulated. Other ap-
proaches to identifying genes that are
critical in primitive erythroid development
have been fruitful. In the mouse, a criti-
cal role for BMP4 in erythroid progenitor
commitment has been revealed through
studies of primitive erythroid differenti-
ation in cultured ES cells. Speci±cally,
hematopoiesis can be blocked at the un-
committed progenitor stage when cells are
cultured in the absence of serum. The ad-
dition of BMP4 to culture media promotes
the expression of
gata1
and primitive
erythrocyte differentiation, whereas block-
ing BMP signaling in erythroid cells by
expressing a dominant-negative BMP re-
ceptor with an erythroid-speci±c promoter
prevents
gata1
expression and erythroid
differentiation. Thus, both
moonshine
and
BMP signaling are required for
gata1
expression
and
for
primitive
erythro-
cyte maturation.
Reductions
in
circulating
primitive
erythrocytes
have
been
observed
in
mouse
embryos
that
are
defective
in some cytokine signaling pathways.
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