176
c. Niehrs et al.
lation. In the zebrafish mutant swirl, a bmp-2 gene is mutated and
embryos show expanded dorsolateral structures at the expense of ventral
ones, both in ectoderm and mesoderm (Kishimoto et al. 1997; Nguyen
et al. 1998). The difference in severity between mouse and fish Bmp-2
mutants may be explained by the fact that swirl is a dominant-negative
mutant, which probably affects the function of redundant BMPs, e.g.,
Bmp-4 (Kishimoto et al. 1997).
In Xenopus a Bmp-4 (and Bmp-7) morphogen system seems also
involved in early neurogenesis, where Bmp-4 inhibits, and chordin,
noggin, andfollistatin promote neuralization (Lamb et al. 1993; Hemmati-Brivanlou et al. 1994; Hawley et al. 1995; Sasai et al. 1995; Wilson
and Hemmati-Brivanlou 1995; Suzuki et al. 1997c). Like in mesodermal
patterning BMP-4 acts in a concentration-dependent manner in neural
induction. With decreasing doses three different ectodermal structures,
epidermis, neural crest/cement gland, and anterior neural tissue, are
induced (Knecht and Harland 1997; Wilson et al. 1997; Marchant et al.
1998). Similar results are observed in zebrafish (Kishimoto et al. 1997;
Neave et al. 1997; Nguyen et al. 1998). Finally, d/v patterning of
endoderm is also regulated by BMP-4 (Sasai et al. 1996). Thus, the
BMP-4 morphogen gradient patterns all three germ layers (De Robertis
and Sasai 1996).
10.4 Downstream of Bmp-4:
X vent Homeoproteins and Smads
An important question is how the quantitative differences in BMP-4
signalling are converted into qualitative discrete cellular responses.
BMP proteins bind to type I (Graff et al. 1994; Suzuki et al. 1994) and
type II BMP (Frisch and Wright 1998) transmembrane receptor serine/threonine kinases which form oligomers upon ligand binding. Following receptor activation, BMP signalling is transduced by members of
the Smad family of DNA binding proteins (Massague et al. 1997). There
are three types of Smads: receptor activated Smads, co-Smads, and
anti-Smads. Receptor activated Smad-} and -5 act as specific substrates
for ligand-activated type II BMP receptor kinases (Thomsen 1996;
Meersman et al. 1997; Suzuki et al. 1997a). The co-Smad-4 forms a
complex with receptor activated Smad-l and -5 upon their phosphoryla-
c. Niehrs et al.
lation. In the zebrafish mutant swirl, a bmp-2 gene is mutated and
embryos show expanded dorsolateral structures at the expense of ventral
ones, both in ectoderm and mesoderm (Kishimoto et al. 1997; Nguyen
et al. 1998). The difference in severity between mouse and fish Bmp-2
mutants may be explained by the fact that swirl is a dominant-negative
mutant, which probably affects the function of redundant BMPs, e.g.,
Bmp-4 (Kishimoto et al. 1997).
In Xenopus a Bmp-4 (and Bmp-7) morphogen system seems also
involved in early neurogenesis, where Bmp-4 inhibits, and chordin,
noggin, andfollistatin promote neuralization (Lamb et al. 1993; Hemmati-Brivanlou et al. 1994; Hawley et al. 1995; Sasai et al. 1995; Wilson
and Hemmati-Brivanlou 1995; Suzuki et al. 1997c). Like in mesodermal
patterning BMP-4 acts in a concentration-dependent manner in neural
induction. With decreasing doses three different ectodermal structures,
epidermis, neural crest/cement gland, and anterior neural tissue, are
induced (Knecht and Harland 1997; Wilson et al. 1997; Marchant et al.
1998). Similar results are observed in zebrafish (Kishimoto et al. 1997;
Neave et al. 1997; Nguyen et al. 1998). Finally, d/v patterning of
endoderm is also regulated by BMP-4 (Sasai et al. 1996). Thus, the
BMP-4 morphogen gradient patterns all three germ layers (De Robertis
and Sasai 1996).
10.4 Downstream of Bmp-4:
X vent Homeoproteins and Smads
An important question is how the quantitative differences in BMP-4
signalling are converted into qualitative discrete cellular responses.
BMP proteins bind to type I (Graff et al. 1994; Suzuki et al. 1994) and
type II BMP (Frisch and Wright 1998) transmembrane receptor serine/threonine kinases which form oligomers upon ligand binding. Following receptor activation, BMP signalling is transduced by members of
the Smad family of DNA binding proteins (Massague et al. 1997). There
are three types of Smads: receptor activated Smads, co-Smads, and
anti-Smads. Receptor activated Smad-} and -5 act as specific substrates
for ligand-activated type II BMP receptor kinases (Thomsen 1996;
Meersman et al. 1997; Suzuki et al. 1997a). The co-Smad-4 forms a
complex with receptor activated Smad-l and -5 upon their phosphoryla-