Cell Signaling During Primitive Hematopoiesis
437
hematopoietic. Gene targeting in mouse
(i.e. the creation of a mouse in which
a gene is ‘‘knocked-out’’ or mutated)
has identiFed genes that are required
for
this
process.
One
such
gene
is
the basic helix–loop–helix transcription
factor
scl/tal1
, which is expressed in the
nascent ventral mesoderm, prior to overt
differentiation of hematopoietic cells in all
vertebrates. Mice that are homozygous for
a nonfunctional allele of
scl
fail to generate
any primitive erythrocytes in otherwise
normally patterned embryos. Analysis of
gene expression in these mutant embryos,
as well as hematopoietic culture assays
using
mutant
tissues
and
cell
lines,
demonstrated that
scl
is required for both
primitive and deFnitive hematopoiesis.
Consistent with these data, overexpression
of
scl
in zebraFsh embryos leads to
excessive commitment of mesoderm to
a primitive hematopoietic fate. Similarly,
overexpression of
scl
in dorsal mesoderm
of
Xenopus
embryos
leads
to
ectopic
production of primitive erythroid cells
without otherwise altering the dorsal fate
of this tissue. Collectively, these data are
consistent with the hypothesis that
scl
functions after the induction and ventral
patterning of the mesoderm to specify
primitive hematopoietic fate.
The transcription factor
lmo2
, which con-
tains LIM protein interaction domains but
no DNA binding domain, is expressed in
the prospective hematopoietic mesoderm
in a pattern similar to
scl
.T
a
rg
e
t
ingo
f
lmo2
in mouse conFrms a role for
lmo2
in speciFcation of primitive and deFni-
tive hematopoietic fate. Overexpression of
lmo2
in
Xenopus
is not sufFcient to induce
ectopic primitive hematopoiesis, whereas,
coexpression of high levels of
lmo2
and
scl
can induce ectopic primitive erythrocytes,
suggesting both factors must be present
for a cell to adopt a hematopoietic fate.
Physical interactions between
lmo2
and
scl
have been detected in mammalian ery-
throid cell lines, suggesting that
scl
and
lmo2
may form transcriptional complexes
that regulate genes required for primitive
hematopoiesis.
The regulatory steps that occur between
ventralizing the mesoderm and expression
of
scl
and
lmo2
are extremely important,
bu
tl
i
t
t
l
ei
skn
owna
b
ou
tth
em
.Inz
e
-
braFsh, a spontaneous mutant,
cloche
,has
been identiFed that may reveal much about
hematopoietic speciFcation during prim-
itive hematopoiesis. In
cloche
mutants,
expression of
scl
and
lmo2
is absent or
severely reduced and the intermediate cell
mass contains no morphological evidence
of the presence of erythroid progenitors.
The gene encoded by
cloche
appears to
act upstream of
scl
since forced expres-
sion of
scl
in
cloche
mutants leads to
partial rescue of primitive erythrocytes.
Thus, identifying the gene that encodes
cloche
will be a critical step towards gain-
ing a complete understanding of the early
events of hematopoietic development, in-
cluding the regulation of genes required
for hematopoietic speciFcation.
2.3
Regulating the Production, Expansion and
Survival of Primitive Erythroid Progenitors
Hematopoietic mesoderm gives rise to
multipotent
and
unipotent
progenitor
cells that must make decisions regarding
whether they should proliferate, undergo
apoptosis, or differentiate. Each of these
decisions is tightly regulated by a combi-
nation of extrinsic and intrinsic signals.
In the mouse, the cytokine
vegf
and its
tyrosine kinase receptor
vegfr2
/
flk1
have
been shown to be required at an early
stage for the initial production of prim-
itive erythroid progenitors. Mice mutant
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