Signalling by TGF-beta family members: short-range effects of Xnr-2 and BMP-4 contrast with the long-range effects of activin.
BACKGROUND
One way of establishing a morphogen gradient in a developing embryo involves the localized synthesis of an inducing molecule followed by its diffusion into surrounding tissues. The morphogen-like effects of the mesoderm-inducing factor activin provide support for this idea in amphibian development. The questions remain, however, of how activin exerts its long-range effects, and whether long-range signalling is a property of all transforming growth factor beta (TGF-beta) family members.


RESULTS
We compare the signalling ranges of activin and two other TGF-beta family members, Xnr-2 and BMP-4. Unlike activin, Xnr-2 and BMP-4 act over short distances. Furthermore, the effects of constitutively active activin receptors are strictly cell-autonomous. These observations suggest that the long-range effects of activin occur through protein diffusion and that "relay' mechanisms are not initiated by any of these TGF-beta family members. Mechanisms limiting the signalling range of Xnr-2 were addressed by studying Xnr-2 processing and secretion. An activin-Xnr-2 fusion protein signals over many cell diameters, suggesting that regulated processing or secretion is one limiting factor. Disaggregation and reaggregation of Xnr-2-producing tissues also extends the range of Xnr-2, suggesting that components of intact tissue restrict spread of the protein.


CONCLUSIONS
The long-range effects of activin are likely to occur through the diffusion of activin protein. The short-range effects of Xnr-2 and BMP-4 emphasize that long-range diffusion is not a general property of TGF-beta-related molecules. Finally, signalling ranges may be regulated by constraints on processing or secretion and by interactions with extracellular components of embryonic tissues.
Jones
C M
CM
Division of Developmental Biology, National Institute for Medical Research, Mill Hill, London, UK. m-jones@nimr.mrc.ac.uk
Armes
N
N
Smith
J C
JC
D030201:Activin Receptors, Type I; D028341:Activins; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005326:Fetal Proteins / Q000378:metabolism; D051956:Goosecoid Protein; D018398:Homeodomain Proteins; D007265:Inhibins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055456:Nodal Signaling Ligands; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins; D000098908:Brachyury Protein
D030201:Activin Receptors, Type I; D028341:Activins; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D051956:Goosecoid Protein; D018398:Homeodomain Proteins; D007265:Inhibins; D055456:Nodal Signaling Ligands; D011506:Proteins; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D000098908:Brachyury Protein; C525810:Bmp4 protein, mouse; C497993:Gsc protein, mouse; C113775:Ndr2 protein, vertebrate; C485173:STK38L protein, Xenopus; C525812:bmp4 protein, Xenopus