Embryonic Patterning of Xenopus Mesoderm by Bmp-4
173
auto-activating (Dale et al. 1992), possibly by an autoregulatory loop
involving Xvent-2 (Onichtchouk et al. 1996; Schmidt et al. 1996), it is
puzzling that the protein should not be acting by a relay with itself.
Clearly, we still know little about the range ofBMP-4 action in vivo.
Like BMP-4, its antagonist Noggin has long-range effects (Fig. 2B).
When noggin mRNA is coinjected with ~-galactosidase and the expression of the Xvent-2 marker gene analyzed, repression of Xvent gene
expression occurs in a halo around the ~-galactosidase-positive cells.
This effect can sweep over most of the embryo at higher doses, suggesting that Noggin can diffuse much further than BMP-4 (Dosch et al.
1997; Jones and Smith 1998).
These results argue for a model (Fig. 3), where positional information in the gastrula marginal zone is provided by graded BMP-4 activity
which is high ventrally and low dorsally. Graded BMP-4 activity is the
result of superimposition of antagonizing BMP-4 and BMP antagonists,
e.g., Noggin, Chordin, and Follistatin. In the dorsolateral domain BMP4 protein is attenuated, allowing for myf-5 expression and muscle differentiation, both of which require BMP signalling. Yet, muscle differentiation and myf-5 expression are repressed by high BMP-4 levels, which
induce blood differentiation and ventral marker gene (Xvent-l) expression. Thus, dorsal, dorsolateral, and lateroventral fate is determined by
distinct BMP-4 concentrations. Although the BMP-4 activity gradient
remains to be visualized by some direct means, both Noggin and BMP-4
are capable of signalling at long range in the marginal zone as would be
expected in this model. Interestingly, in the animal cap BMP-4 appears
to have short-range action (Jones et al. 1996). This suggests regional
differences in diffusibility of BMP-4. The shape of the BMP-4 activity
gradient may therefore be influenced by these differences, possibly
mediated by the extracellular matrix.
The BMP antagonists Noggin, Chordin, and Follistatin have all the
properties of a bona fide inducer of dorsal and dorsolateral fate. Given
the observation, however, that these BMP antagonists function by sequestering and neutralizing BMP proteins (Piccolo et al. 1996; Zimmerman et al. 1996; Fainsod et al. 1997; lemura et al. 1998), they may not
be considered mechanistically instructive inducers unless a separate
receptor is identified. Rather, they modify the positional information
which is provided by BMP signalling, thus generating graded activity of
the BMP-4 morphogen. In this mechanistic view, the organizer may
173
auto-activating (Dale et al. 1992), possibly by an autoregulatory loop
involving Xvent-2 (Onichtchouk et al. 1996; Schmidt et al. 1996), it is
puzzling that the protein should not be acting by a relay with itself.
Clearly, we still know little about the range ofBMP-4 action in vivo.
Like BMP-4, its antagonist Noggin has long-range effects (Fig. 2B).
When noggin mRNA is coinjected with ~-galactosidase and the expression of the Xvent-2 marker gene analyzed, repression of Xvent gene
expression occurs in a halo around the ~-galactosidase-positive cells.
This effect can sweep over most of the embryo at higher doses, suggesting that Noggin can diffuse much further than BMP-4 (Dosch et al.
1997; Jones and Smith 1998).
These results argue for a model (Fig. 3), where positional information in the gastrula marginal zone is provided by graded BMP-4 activity
which is high ventrally and low dorsally. Graded BMP-4 activity is the
result of superimposition of antagonizing BMP-4 and BMP antagonists,
e.g., Noggin, Chordin, and Follistatin. In the dorsolateral domain BMP4 protein is attenuated, allowing for myf-5 expression and muscle differentiation, both of which require BMP signalling. Yet, muscle differentiation and myf-5 expression are repressed by high BMP-4 levels, which
induce blood differentiation and ventral marker gene (Xvent-l) expression. Thus, dorsal, dorsolateral, and lateroventral fate is determined by
distinct BMP-4 concentrations. Although the BMP-4 activity gradient
remains to be visualized by some direct means, both Noggin and BMP-4
are capable of signalling at long range in the marginal zone as would be
expected in this model. Interestingly, in the animal cap BMP-4 appears
to have short-range action (Jones et al. 1996). This suggests regional
differences in diffusibility of BMP-4. The shape of the BMP-4 activity
gradient may therefore be influenced by these differences, possibly
mediated by the extracellular matrix.
The BMP antagonists Noggin, Chordin, and Follistatin have all the
properties of a bona fide inducer of dorsal and dorsolateral fate. Given
the observation, however, that these BMP antagonists function by sequestering and neutralizing BMP proteins (Piccolo et al. 1996; Zimmerman et al. 1996; Fainsod et al. 1997; lemura et al. 1998), they may not
be considered mechanistically instructive inducers unless a separate
receptor is identified. Rather, they modify the positional information
which is provided by BMP signalling, thus generating graded activity of
the BMP-4 morphogen. In this mechanistic view, the organizer may