Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

Development. 2017 Aug 1;144(15):2824-2836. doi: 10.1242/dev.150680. Epub 2017 Jul 10.

Abstract

During development and homeostasis, precise control of Wnt/β-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/β-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/β-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/β-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.

Keywords: Lrp4; Mouse; Sostdc1; Tooth; Wnt/β-catenin signaling.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Morphogenetic Proteins / deficiency
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-5 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Mice
  • Mice, Mutant Strains
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Tooth / embryology*
  • Tooth / metabolism*
  • Tooth / pathology
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / physiology
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp4 protein, mouse
  • Lrp5 protein, mouse
  • Lrp6 protein, mouse
  • Receptors, LDL
  • Sostdc1 protein, mouse
  • beta Catenin