Developmental Biology

L.B. Zimmerman, J.M. De Jesús-Escobar, R.M. Harland, "The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4," Cell, 86:599-606, 1996. (Cited in more than 180 papers since publication) Comments by Richard M. Harland, Choh Hao Li professor of biochemistry and molecular biology, University of California, Berkeley Richard M. Harland Researchers had long suspected that the protein noggin's interaction with bone morphogenetic proteins (BMPs) dictated developmental decisions such as whether an embryonic cell should form epidermal tissue or build the neural plate. "But the way it did so was not clear," recalls Richard M. Harland. "It might be acting through its own cell surface receptors and acting inside the cell pathway through its own transduction process." However, experiments in fruit flies done by Chip Ferguson and colleagues at the University of Chicago provided an important clue.1 In Drosophila assays, frog-derived noggin could block the fly version of BMP, a dorsally produced growth factor called dpp. "If you could activate signaling downstream of the cell surface, noggin would have no effect," Harland notes. "That suggested strongly that noggin might work outside the cell." That hunch was solidified through a series of biochemical assays, reported in this paper. The assays revealed that noggin binds both tightly and directly to BMP-4 and thereby prevents BMPs from activating their receptors. In early development this mechanism is used to determine whether cells become nervous system or epidermis. "If BMP signaling is active, the decision is then toward epidermis," Harland comments. "If BMP signaling is blocked, then the decision is toward neural plate." Harland suspects this paper has been cited often because regulation of BMP signaling is important throughout development--not just during the embryonic stage. "BMP signaling is ubiquitous in biology. There are a lot of cases where BMPs are important in blocking and activating different cellular decisions." Since this paper, other researchers have used noggin as a tool to block BMP signaling and thus illustrate the many roles that BMPs play. "This protein noggin is made by a variety of different tissues at different times during development." In addition to the epidermal vs. neural plate choice, BMP activation also dictates blood cell formation, neural tube differentiation,2 and skeletal growth, among others. For many of these processes noggin is probably a redundant signal. For example, chordin (see Hot Paper below) similarly binds to BMP-4, even though that protein differs both structurally and genetically from noggin. "There are a large number of BMP antagonists," Harland notes. "We have been working with other BMP antagonists, which are structurally unrelated to noggin but seem to have very similar functions." Harland says that the large family of BMPs are structurally quite conserved but have varied functions, while BMP inhibitors--such as noggin and chordin--are structurally diverse but share at least some functions.3 He anticipates that researchers will add more members to the BMP inhibitor family. However, the tougher task might be elucidating how these proteins differ in function, if at all. The inhibitors may be redundant or they may have subtly different functions. Recent mouse knockout experiments illustrate the complexity. For instance, in mice missing the gene coding for noggin, neural induction wasn't impeded, but later developmental steps were.4 Before BMP antagonists can be used in clinical applications, researchers must pick apart whether they act alone, at different stages, or in different tissues. "Are there parallel biochemical pathways, controlled by separate but related proteins?" Harland queries. "There may be multiple redundant signals." S.A. Holley et al., "The Xenopus dorsalizing factor noggin ventralizes Drosophila embryos by preventing dpp from activating its receptor," Cell, 86:607-17, 1996. J.A. McMahon et al., "Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite," Genes and Development, 12:1438-52, May 15, 1998. D.R. Hsu et al., "The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities," Molecular Cell, 1:673-83, April 1998. L.J. Brunet et al., "Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton," Science, 280:1455-7, May 29, 1998.

Developmental Biology

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