Developmental Biology

S. Piccolo, Y. Sasai, B. Lu, E.M. De Robertis, "Dorsoventral patterning in Xenopus: Inhibition of ventral signals by direct binding of chordin to BMP-4," Cell, 86:589-98, 1996. (Cited in more than 170 papers since publication) Comments by Eddy M. De Robertis, Investigator, Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles Eddy M. De Robertis In 1924, two scientists identified a small group of embryonic cells that tell their neighbors what types of tissues to form.1 Scientists have since worked to discern the precise molecular parts of this machinery, called the Spemann organizer. The pieces of those molecular mechanisms have become better known in the past five years. A number of organizer-specific genes such as the homeobox gene goosecoid (gsc) and factors secreted by the Spemann organizer, including noggin and chordin, have been identified. However, the precise ways these genes and proteins interact to control development had eluded researchers. Eddy M. De Robertis and colleagues learned that chordin, like noggin (see Hot Paper above) secreted by the Spemann organizer, was an antagonist of BMP-4,2 which is expressed in a wide ventral region of the embryo. But they didn't know how. "When we isolated this novel molecule, we expected that it would signal, through a receptor pathway, perhaps," De Robertis recalls. Assays reported in this paper revealed that chordin, like noggin, turned off BMP-4 activity by binding to that growth factor rather than to its receptors, as they had predicted. Finding out why the same part of the embryo--the Spemann organizer--produced noggin, chordin, follistatin, and likely other BMP antagonists--poses a challenge to biologists. Why so many inhibitors? "That's a very difficult question," admits De Robertis. "It could be that there are different affinities for different BMPs. That's one possibility. The other possibility is that this is so important that you have to have it under very controlled circumstances. But it's a huge mystery." The seeming redundancy also presents some grounds for interesting evolutionary speculation, notes De Robertis: "It might be very difficult to evolve new signaling pathways," De Robertis continues. "On the other hand, it might be possible to evolve inhibitors perhaps more easily. All you need to do is throw a spanner in the works. All you need to do is down-regulate something. And maybe you can do that without great precision or being very efficient about it." Since this paper, De Robertis and colleagues have found another, possibly nonredundant, role for chordin. The researchers identified a protease that eventually cleaves the protein, which then releases active BMP-4 from the previously inactive complex.3 De Robertis calls that protease "an inhibitor of an inhibitor." This raises the question of the exact role the cleaving protease plays in development: "Are these truly plain inhibitors that bind to the growth factor, or are they involved in somehow transporting the growth factor to a different place in the body?" Answering that question could be difficult, De Robertis thinks. Most signaling research maps out cues from a cell's membrane to its nucleus. Intercellular signaling, by comparison, remains mostly uncharted territory. "These things are probably an integral part of how cells are signaling in extracellular space," De Robertis says of the proteases. Understanding that signaling process may help reveal clinical applications for both chordin and noggin--both of which have been patented, De Robertis concludes. H. Spemann and H. Mangold, "Uber induktion von embryonalagen durch implantation artfremder organisatoren," Roux Archiv für Entwicklungsmechanik der Organismen, 100:599-638, 1924. Y. Sasai et al., "Regulation of neural induction by the chd and BMP-4 antagonistic patterning signals in Xenopus," Nature, 376:333-6, 1995. S. Piccolo et al., "Cleavage of chordin by xolloid metalloprotease suggests a role for proteolytic processing in the regulation of Spemann organizer activity," Cell, 91:407-16, 1997.

Developmental Biology

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