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We have identified a novel mode of signaling pathway integration\/coordination that occurs outside cells during development that involves an LDL receptor family member. Physical interaction between an extracellular protein (Wise) that binds BMP ligands and an Lrp receptor (Lrp4) that modulates Wnt signaling, acts to link these two pathways. Mutations in either <jats:italic>Wise<\/jats:italic> or <jats:italic>Lrp4<\/jats:italic> in mice produce multiple, but identical abnormalities in tooth development that are linked to alterations in BMP and Wnt signaling. Teeth, in common with many other organs, develop by a series of epithelial\u2013mesenchymal interactions, orchestrated by multiple cell signaling pathways. In tooth development, <jats:italic>Lrp4<\/jats:italic> is expressed exclusively in epithelial cells and <jats:italic>Wise<\/jats:italic> mainly in mesenchymal cells. Our hypothesis, based on the mutant phenotypes, cell signaling activity changes and biochemical interactions between Wise and Lrp4 proteins, is that Wise and Lrp4 together act as an extracellular mechanism of coordinating BMP and Wnt signaling activities in epithelial\u2013mesenchymal cell communication during development. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.33372","type":"journal-article","created":{"date-parts":[[2010,4,29]],"date-time":"2010-04-29T19:20:20Z","timestamp":1272568820000},"page":"2974-2983","source":"Crossref","is-referenced-by-count":32,"title":["Lrp4: A novel modulator of extracellular signaling in craniofacial 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