440
Cell Signaling During Primitive Hematopoiesis
Historically, cytokine function in primitive
hematopoiesis has largely been ignored
or dismissed, most likely because only
a
subset
of
differentiating
primitive
erythrocytes fail to survive in known
cytokine signaling mutants. Moreover,
in
many
cases,
the
embryos
can
survive to stages where more drastic
effects on deFnitive hematopoiesis are
observed.
The
erythropoietin
receptor
(EpoR),
a
member
of
the
cytokine
receptor
superfamily,
is
expressed
in
the early mouse yolk sac hematopoietic
mesoderm,
before
erythroblasts
are
detectable,
and
is
also
expressed
in
developing primitive erythroid cells at
later
stages
of
development.
In
yolk
sac cultures, addition of EPO to the
culture
media
increases
the
number
of
primitive
erythrocytes.
Conversely,
introduction of antisense oligonulceotides
that
block
epoR
expression
reduce
the number of differentiated primitive
erythrocytes. Mice that are homozygous
null for the
epoR
gene apparently initiate
hematopoietic development normally, as
normal
numbers
of
erythroblasts
are
present in the yolk sac at E9.5 (at this
stage about half of the erythroblasts have
entered circulation). However, by E10.5,
circulating primitive erythroid cells are
reduced by
80%. In the remaining
circulating erythroid cells, differentiation
appears to occur normally, suggesting that
Epo signaling is speciFcally required for
erythroblast proliferation and/or survival.
A two- to threefold reduction in circulating
erythrocytes has also been reported in
mouse E12 embryos that do not express
c-kit
,
a
tyrosine
kinase
receptor
that
binds stem cell factor/kit ligand. Analysis
prior to E12 has not been reported,
but
a
decrease
in
circulating
blood
erythrocytes at this stage may indicate
a deFcit in primitive erythroid survival
or proliferation. The Janus Kinase (Jak)
family of cytoplasmic tyrosine kinases
mediates
signaling
through
cytokine
superfamily receptors, including EpoR
as
well
as
tyrosine
kinase
receptors,
including c-Kit. A signiFcant reduction
in the number of circulating primitive
erythrocytes in
jak2
/
mice has been
reported. ±inally, TG±-
β
1 appears to also
play a role in the proliferation of primitive
erythroid progenitors. In some
tgf-
β
1
/
embryos, a large reduction in circulating
erythroid cells is observed after E9.5.
Together, these data not only highlight
the importance of cytokines in primitive
erythroid cells but also suggest that some
profound differences in cell signaling
exist between primitive and deFnitive
hematopoiesis. A number of zebraFsh
mutants that similarly arrest primitive
erythroid development after erythroblasts
have entered the bloodstream have been
identiFed and characterized. In these
mutants, normal numbers of erythroblasts
enter circulation, but they subsequently
fail to proliferate, and in some cases,
they also fail to maintain hemoglobin
expression and do not fully differentiate.
Retinoic acid may also play an im-
portant, concentration-dependent role in
primitive erythroid cell differentiation. Al-
though numerous retinoic acid receptors
have been knocked-out in the mouse with-
out any major effects on primitive or
deFnitive hematopoiesis, increases or de-
creases in retinoic acid do affect primitive
erythropoiesis in
Xenopus
and quail em-
bryos, respectively. ±or example, incubat-
ing
Xenopus
embryos in retinoic acid leads
to defects in primitive erythrocyte differ-
entiation and survival without an apparent
effect on hematopoietic speciFcation. Vita-
min A-deFcient quail embryos maintain
expression of
gata1
in yolk sac-derived
erythroblasts, but form fewer primitive
previous page 1114 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1116 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off