Embryonic Patterning of Xenopus Mesoderm by Bmp-4
171
If Bmp-4 acts as a vertebrate morphogen for mesodermal patterning
it should fulfill certain criteria in addition to being expressed at the right
time and place: (a) it should elicit dose-dependent effects, (b) there
should be a graded requirement for Bmp-4, (c) its activity should be
graded in vivo, and (d) indirect (relay) effects should be excluded.
We have investigated the possibility that Bmp-4 functions dose-dependently in d/v patterning of Xenopus mesoderm at the gastrnla stage
(Dosch et al. 1997). In marginal zone explants, Bmp-4 ventralizes dorsal
mesoderm in a dose-dependent manner, from notochord, muscle,
pronephros to blood. Inversely, a dominant-negative BMP receptor dorsalizes ventral mesoderm dose-dependently from blood, pronephros,
muscle to notochord. This dose-dependent effect of BMP signalling can
be already observed at the gastrula stage using marker gene expression.
Most instructive is the response of the myogenic gene myf-5, expressed
in two dorsolateral stripes corresponding to prospective muscle. These
stripes are the result of a response window corresponding to low BMP
signalling, since either lower or higher BMP signalling shuts off myf-5
expression (Fig. 2A). Thus, for muscle fate a particular threshold of
BMP signalling is required (Dosch et al. 1997; Jones and Smith 1998).
These results, as well as the response of other marker genes, indicate
that different Bmp-4 doses are both necessary and sufficient for patterning of at least three domains in the gastrula marginal zone, as well as for
terminal differentiation into four mesodermal tadpole tissues. There are
possibly additional domains in the gastrula marginal zone, e.g., a lateral
domain corresponding to future pronephric mesoderm. Recently, a
novel ventral domain was discovered marked by the expression of
sizzled (Salic et al. 1997).
Is there graded BMP-4 signalling in vivo? Although Bmp-4 and
Bmp-7 are expressed at the right time and place to pattern mesoderm in
the early gastrula, their mRNAs do not appear to be distributed in a
graded fashion in the marginal zone (Fainsod et al. 1994; Hawley et al.
1995; Schmidt et al. 1995b; our unpublished data). Instead, BMP activity, rather than protein, appears to be graded due to antagonizing action
of noggin, chordin, andfollistatin (Ferguson 1996; Hogan 1996; Holley
et al. 1996; Piccolo et al. 1996; Zimmerman et al. 1996). Indeed,
Xenopus noggin has dose-dependent effects on mesodermal
(ReemKalma et al. 1995; Dosch et al. 1997; Jones and Smith 1998) and
neural patterning (Knecht and Harland 1997; Wilson et al. 1997; Mar-
171
If Bmp-4 acts as a vertebrate morphogen for mesodermal patterning
it should fulfill certain criteria in addition to being expressed at the right
time and place: (a) it should elicit dose-dependent effects, (b) there
should be a graded requirement for Bmp-4, (c) its activity should be
graded in vivo, and (d) indirect (relay) effects should be excluded.
We have investigated the possibility that Bmp-4 functions dose-dependently in d/v patterning of Xenopus mesoderm at the gastrnla stage
(Dosch et al. 1997). In marginal zone explants, Bmp-4 ventralizes dorsal
mesoderm in a dose-dependent manner, from notochord, muscle,
pronephros to blood. Inversely, a dominant-negative BMP receptor dorsalizes ventral mesoderm dose-dependently from blood, pronephros,
muscle to notochord. This dose-dependent effect of BMP signalling can
be already observed at the gastrula stage using marker gene expression.
Most instructive is the response of the myogenic gene myf-5, expressed
in two dorsolateral stripes corresponding to prospective muscle. These
stripes are the result of a response window corresponding to low BMP
signalling, since either lower or higher BMP signalling shuts off myf-5
expression (Fig. 2A). Thus, for muscle fate a particular threshold of
BMP signalling is required (Dosch et al. 1997; Jones and Smith 1998).
These results, as well as the response of other marker genes, indicate
that different Bmp-4 doses are both necessary and sufficient for patterning of at least three domains in the gastrula marginal zone, as well as for
terminal differentiation into four mesodermal tadpole tissues. There are
possibly additional domains in the gastrula marginal zone, e.g., a lateral
domain corresponding to future pronephric mesoderm. Recently, a
novel ventral domain was discovered marked by the expression of
sizzled (Salic et al. 1997).
Is there graded BMP-4 signalling in vivo? Although Bmp-4 and
Bmp-7 are expressed at the right time and place to pattern mesoderm in
the early gastrula, their mRNAs do not appear to be distributed in a
graded fashion in the marginal zone (Fainsod et al. 1994; Hawley et al.
1995; Schmidt et al. 1995b; our unpublished data). Instead, BMP activity, rather than protein, appears to be graded due to antagonizing action
of noggin, chordin, andfollistatin (Ferguson 1996; Hogan 1996; Holley
et al. 1996; Piccolo et al. 1996; Zimmerman et al. 1996). Indeed,
Xenopus noggin has dose-dependent effects on mesodermal
(ReemKalma et al. 1995; Dosch et al. 1997; Jones and Smith 1998) and
neural patterning (Knecht and Harland 1997; Wilson et al. 1997; Mar-