436
Cell Signaling During Primitive Hematopoiesis
little is currently known about primitive
leukocyte development.
2.1
The Signal to become Ventral
Primitive and defnitive hematopoietic
cells are derived From mesoderm, the germ
layer oF the embryo that gives rise to noto-
chord, kidney, muscle, bone, blood, blood
vessels, and heart. Early in development,
mesoderm is specifed and is subsequently
patterned along the dorsal/ventral (D/V;
back/belly) axis. The dorsalmost meso-
derm is the notochord, whereas the ven-
tralmost mesoderm is the primitive blood.
D/V patterning oF mesoderm is largely
regulated by bone morphogenetic proteins
(BMPs), secreted signaling molecules oF
the transForming growth Factor-
β
(TG±-
β
)
superFamily. Numerous BMPs have been
identifed in vertebrates; however, existing
evidence suggests that
bmp2
,
4
,and
7
are
most likely to participate in D/V patterning
oF nascent mesoderm.
BMPs are proposed to act as mor-
phogens in patterning the mesoderm. A
morphogen is a substance that is present
in a gradient and elicits a range oF spe-
cifc developmental outcomes (mesoderm
patterning in this case) in a concentration-
dependent manner. Convincing evidence
in support oF this theory comes From stud-
ies oF
Xenopus
and zebrafsh embryos in
which BMP signaling is incrementally in-
creased or decreased. Increasing the dose
oF BMP4 in developing embryos (by inject-
ing increasing amounts oF
bmp4
mRNA
into embryos) leads to Formation oF meso-
derm with increasing ventral character at
the expense oF dorsal mesoderm. Con-
versely, decreasing the amount oF BMP4
signaling (by injecting increasing amounts
oF mRNA encoding a dominant-negative
BMP receptor) leads to the production oF
increasingly dorsal mesoderm at the ex-
pense oF ventral mesoderm. Thus, high
levels oF BMP signaling speciFy the most
ventral Fate (primitive blood), lower levels
oF BMP signaling speciFy an intermedi-
ate cell Fate (pronephros, the Functional
equivalent oF kidney, and defnitive blood),
and low or absent levels oF BMP signaling
speciFy the most dorsal cell Fate (notochord,
somites) within the mesoderm. Similarly,
in zebrafsh, a series oF BMP signaling mu-
tants has been generated From large-scale
mutagenesis screens. Those embryos with
the most severe losses oF BMP signaling
display the most dorsalized mesodermal
phenotypes whereas those with the most
active BMP signaling display the most ven-
tralized phenotypes. In mouse,
bmp4
,bu
t
not
bmp2
or
bmp7
, appears to play a role in
the specifcation oF ventral mesoderm. In
theabsenceo
F
bmp4
, ventral derivatives,
including primitive blood and endothe-
lium, Fail to Form in the yolk sac. Many
questions remain as to how BMPs reg-
ulate mesodermal pattern. ±or instance,
the direct transcriptional targets oF the
BMP signaling pathway have not been
well characterized. In addition, it is not
yet clear how quantitative changes in BMP
signaling diFFerentially regulate expression
oF these target genes. ±urthermore, the
timing oF BMP action on D/V patterning
oF each mesodermal type during early de-
velopment and whether BMP acts on each
mesodermal type directly or indirectly (For
instance, through signaling in surround-
ing tissues) is not well characterized.
2.2
Specifying Primitive Hematopoietic Cell
Fate
AFter the nascent mesoderm has been
patterned along the D/V axis, a subset
oF the ventral mesoderm is specifed as
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