168
C. Niehrs et al.
A number of studies have suggested that the ventral marginal zone
not only requires active signals for the specification of the ventral state,
but signals to antagonize the organizer. Firstly, the ventral marginal zone
expresses peptide growth factors, Xwnt-8 and bone morphogenetic proteins -4 and -7 (Bmp-41-7), that are able to override dorsal mesodermal
specification (Koster et al. 1991; Dale et al. 1992; Jones et al. 1992;
Christian and Moon 1993; Fainsod et al. 1994; Hemmati-Brivanlou and
Thomsen 1995; Schmidt et al. 1995b; Wang et al. 1997). Secondly,
inhibition of BMP signalling in Xenopus by microinjection of mRNA
coding for a dominant-negative BMP receptor (Maeno et al. 1994;
Suzuki et al. 1994; Ishikawa et al. 1995), Bmp-4 antisense mRNA
(Steinbeisser et al. 1995), or dominant-negative BMPs (Hawley et al.
1995; Nishimatsu and Thomsen 1998) leads to dorsalization of ventral
mesoderm. These findings suggested that marginal zone patterning may
be the result of antagonizing dorsal and ventral signals (Sive 1993;
Harland 1994; De Robertis and Sasai 1996).
Indeed, the organizer secretes three dorsalizing signals, Noggin
(Smith and Harland 1992; Smith et al. 1993) Chordin (Sasai et al. 1994;
Sasai et al. 1995), and Follistatin (Hemmati-Brivanlou et al. 1994). All
are expressed in the organizer and, when overexpressed in ventral mesoderm, lead to dorsalization. These proteins do not seem to transmit
signals through their own receptors. Instead, they directly bind to BMP2 and BMP-4, thereby inactivating them (Piccolo et al. 1996; Zimmerman et al. 1996; Fainsod et al. 1997; lemura et al. 1998). Thus, one
mechanism for dorsalization is to antagonize ventra1izing BMP signals
in the marginal zone.
The role of BMPs and its antagonists appears to be evolutionarily
conserved between arthropods and vertebrates (Fig. IB). Chordin is
homologous to the Drosophila gene short gastrulation (sog), which
plays an important role in the d/v development of the fly blastoderm. In
Drosophila, sog antagonizes the Bmp-4 homolog decapentaplegic (dpp)
(Francois et al. 1994), and overexpression of Drosophila sog in Xenopus
has effects similar to overexpression of chordin (Holley et al. 1995;
Schmidt et al. 1995a). The astacin protease tolloid is involved both in
Drosophila and in Xenopus in antagonizing chordin/sog function by
cleaving chordinIBMP complexes (Marques et al. 1997; Piccolo et al.
1997). Dpp functions as a morphogen, and regulates in a dose-dependent fashion the development of ectodermal structures in the fly embryo
C. Niehrs et al.
A number of studies have suggested that the ventral marginal zone
not only requires active signals for the specification of the ventral state,
but signals to antagonize the organizer. Firstly, the ventral marginal zone
expresses peptide growth factors, Xwnt-8 and bone morphogenetic proteins -4 and -7 (Bmp-41-7), that are able to override dorsal mesodermal
specification (Koster et al. 1991; Dale et al. 1992; Jones et al. 1992;
Christian and Moon 1993; Fainsod et al. 1994; Hemmati-Brivanlou and
Thomsen 1995; Schmidt et al. 1995b; Wang et al. 1997). Secondly,
inhibition of BMP signalling in Xenopus by microinjection of mRNA
coding for a dominant-negative BMP receptor (Maeno et al. 1994;
Suzuki et al. 1994; Ishikawa et al. 1995), Bmp-4 antisense mRNA
(Steinbeisser et al. 1995), or dominant-negative BMPs (Hawley et al.
1995; Nishimatsu and Thomsen 1998) leads to dorsalization of ventral
mesoderm. These findings suggested that marginal zone patterning may
be the result of antagonizing dorsal and ventral signals (Sive 1993;
Harland 1994; De Robertis and Sasai 1996).
Indeed, the organizer secretes three dorsalizing signals, Noggin
(Smith and Harland 1992; Smith et al. 1993) Chordin (Sasai et al. 1994;
Sasai et al. 1995), and Follistatin (Hemmati-Brivanlou et al. 1994). All
are expressed in the organizer and, when overexpressed in ventral mesoderm, lead to dorsalization. These proteins do not seem to transmit
signals through their own receptors. Instead, they directly bind to BMP2 and BMP-4, thereby inactivating them (Piccolo et al. 1996; Zimmerman et al. 1996; Fainsod et al. 1997; lemura et al. 1998). Thus, one
mechanism for dorsalization is to antagonize ventra1izing BMP signals
in the marginal zone.
The role of BMPs and its antagonists appears to be evolutionarily
conserved between arthropods and vertebrates (Fig. IB). Chordin is
homologous to the Drosophila gene short gastrulation (sog), which
plays an important role in the d/v development of the fly blastoderm. In
Drosophila, sog antagonizes the Bmp-4 homolog decapentaplegic (dpp)
(Francois et al. 1994), and overexpression of Drosophila sog in Xenopus
has effects similar to overexpression of chordin (Holley et al. 1995;
Schmidt et al. 1995a). The astacin protease tolloid is involved both in
Drosophila and in Xenopus in antagonizing chordin/sog function by
cleaving chordinIBMP complexes (Marques et al. 1997; Piccolo et al.
1997). Dpp functions as a morphogen, and regulates in a dose-dependent fashion the development of ectodermal structures in the fly embryo