Embryonic Patterning of Xenopus Mesoderm by Bmp-4
177
tion which is required for transcriptional activation of Smad target genes
(Chen et al. 1997; Liu et al. 1997; Zhang et al. 1997). The BMP-specific
Smad-1 may compete with the activin-specific Smad-2 for binding of
Smad-4, suggesting an intracellular antagonism between the two signalling pathways (Candia et al. 1997). Finally, anti-Smad-6 and -7 serve to
inhibit BMP signalling and seem to be involved in negative feedback
regulation (Casellas and Hemmati-Brivanlou 1998; Hata et al. 1998).
The disruption of Smad function is the basis of a number of cancers
in man (Massague et al. 1997). Smad-4 is a tumor suppressor gene
which is disrupted in a large proportion of pancreatic carcinomas. Smad2 disruption correlates with head and neck carcinomas. Targeted disruption of Smad-3 in mice leads to colon carcinoma (Zhu et al. 1998).
Together with the observation that BMPs are expressed in many adult
organs, this suggests that components of the BMP pathway are prime
candidates for genes implicated in a variety of cancers.
Interestingly, receptor activated Smads are able to act in a dose-dependent fashion (Graff et al. 1996; Wilson et al. 1997). Thus, the
conversion of positional information into qualitatively distinct responses is likely to occur at the level of induced target genes which
mediate BMP signalling. In the Drosophila wing, the transcription
factors spa It, spalt-related and optomotor blind (omb) are expressed in
nested domains whose boundaries of expression are a function of the
distance from a local Dpp source (Lecuit et al. 1996; Nellen et al. 1996).
These genes have important roles in mediating the transcriptional effects
at distinct concentration thresholds downstream of the dpp morphogen
(De Celis et al. 1996; Grimm and Pflugfelder 1996; Sturtevant et al.
1997).
In Xenopus, candidate transcriptional targets that mediate the effects
of Bmp-4 are msxl in ectoderm (Suzuki et al. 1997) and the Xvent
homeobox genes in ecto- and mesoderm. Xvent-l (Gawantka et al.
1995), also called PV 1 (Tidman-Ault et al. 1996), Xvent-2
(Onichtchouk et al. 1996), also called Xbrl, and Vox and Xom (Papalopu1u and Kintner 1996; Schmidt et al. 1996; Ladher et al. 1996; see
Lemaire 1996 for review), are overlappingly expressed in the gastrula
marginal zone but show distinct dorsal boundaries of expression
(Fig. 4B,C) (Onichtchouk et al. 1996). Similar to the situation in Drosophila where the anterior expression boundaries of omb and spalt are
regulated by the distance from the dpp source, the different dorsal
177
tion which is required for transcriptional activation of Smad target genes
(Chen et al. 1997; Liu et al. 1997; Zhang et al. 1997). The BMP-specific
Smad-1 may compete with the activin-specific Smad-2 for binding of
Smad-4, suggesting an intracellular antagonism between the two signalling pathways (Candia et al. 1997). Finally, anti-Smad-6 and -7 serve to
inhibit BMP signalling and seem to be involved in negative feedback
regulation (Casellas and Hemmati-Brivanlou 1998; Hata et al. 1998).
The disruption of Smad function is the basis of a number of cancers
in man (Massague et al. 1997). Smad-4 is a tumor suppressor gene
which is disrupted in a large proportion of pancreatic carcinomas. Smad2 disruption correlates with head and neck carcinomas. Targeted disruption of Smad-3 in mice leads to colon carcinoma (Zhu et al. 1998).
Together with the observation that BMPs are expressed in many adult
organs, this suggests that components of the BMP pathway are prime
candidates for genes implicated in a variety of cancers.
Interestingly, receptor activated Smads are able to act in a dose-dependent fashion (Graff et al. 1996; Wilson et al. 1997). Thus, the
conversion of positional information into qualitatively distinct responses is likely to occur at the level of induced target genes which
mediate BMP signalling. In the Drosophila wing, the transcription
factors spa It, spalt-related and optomotor blind (omb) are expressed in
nested domains whose boundaries of expression are a function of the
distance from a local Dpp source (Lecuit et al. 1996; Nellen et al. 1996).
These genes have important roles in mediating the transcriptional effects
at distinct concentration thresholds downstream of the dpp morphogen
(De Celis et al. 1996; Grimm and Pflugfelder 1996; Sturtevant et al.
1997).
In Xenopus, candidate transcriptional targets that mediate the effects
of Bmp-4 are msxl in ectoderm (Suzuki et al. 1997) and the Xvent
homeobox genes in ecto- and mesoderm. Xvent-l (Gawantka et al.
1995), also called PV 1 (Tidman-Ault et al. 1996), Xvent-2
(Onichtchouk et al. 1996), also called Xbrl, and Vox and Xom (Papalopu1u and Kintner 1996; Schmidt et al. 1996; Ladher et al. 1996; see
Lemaire 1996 for review), are overlappingly expressed in the gastrula
marginal zone but show distinct dorsal boundaries of expression
(Fig. 4B,C) (Onichtchouk et al. 1996). Similar to the situation in Drosophila where the anterior expression boundaries of omb and spalt are
regulated by the distance from the dpp source, the different dorsal