C M Jones1, N Armes, J C Smith. 1. Division of Developmental Biology, National Institute for Medical Research, Mill Hill, London, UK. m-jones@nimr.mrc.ac.uk
Abstract
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.
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.