Lrp4: A novel modulator of extracellular signaling in craniofacial organogenesis

Atsushi Ohazama, Thantrira Porntaveetus, Masato S. Ota, Joachim Herz, Paul T. Sharpe

Research output: Contribution to journalReview articlepeer-review

27 Scopus citations


The low-density lipoprotein (LDL) receptor family is a large evolutionarily conserved group of transmembrane proteins. It has been shown that LDL receptor family members can also function as direct signal transducers or modulators for a broad range of cellular signaling pathways. 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 Wise or Lrp4 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-mesenchymal interactions, orchestrated by multiple cell signaling pathways. In tooth development, Lrp4 is expressed exclusively in epithelial cells and Wise 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-mesenchymal cell communication during development.

Original languageEnglish (US)
Pages (from-to)2974-2983
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume152 A
Issue number12
StatePublished - Dec 2010


  • Bmp
  • Fusion tooth
  • Grooved incisor
  • Lrp4
  • Palatal rugae
  • Shh
  • Supernumerary tooth
  • Tooth development
  • Tooth number
  • Wise
  • Wnt

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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