Neogenin Regulation of BMP-induced Canonical Smad Signaling and Endochondral Bone Formation

Dev Cell. 2010 Jul 20;19(1):90-102. doi: 10.1016/j.devcel.2010.06.016.

Abstract

Neogenin has been identified as a receptor for the neuronal axon guidance cues netrins and RGMs (repulsive guidance molecules). Here we provide evidence for neogenin in regulating endochondral bone development and BMP (bone morphogenetic protein) signaling. Neogenin-deficient mice were impaired in digit/limb development and endochondral ossification. BMP2 induction of Smad1/5/8 phosphorylation and Runx2 expression, but not noncanonical p38 MAPK activation, was reduced in chondrocytes from neogenin mutant mice. BMP receptor association with membrane microdomains, which is necessary for BMP signaling to Smad, but not p38 MAPK, was diminished in neogenin-deficient chondrocytes. Furthermore, RGMs appear to mediate neogenin interaction with BMP receptors in chondrocytes. Taken together, our results indicate that neogenin promotes chondrogenesis in vitro and in vivo, revealing an unexpected mechanism underlying neogenin regulation of BMP signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Development / genetics
  • Bone Development / physiology*
  • Bone Morphogenetic Protein 2 / pharmacology
  • Bone Morphogenetic Protein Receptors / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / physiology*
  • Cell Differentiation
  • Cell Proliferation
  • Chondrocytes / cytology
  • Chondrocytes / drug effects
  • Chondrocytes / physiology
  • Chondrogenesis / drug effects
  • Chondrogenesis / genetics
  • Chondrogenesis / physiology*
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Female
  • Growth Plate / embryology
  • Growth Plate / metabolism
  • Membrane Microdomains / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Phosphorylation
  • Pregnancy
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Smad Proteins / genetics
  • Smad Proteins / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Core Binding Factor Alpha 1 Subunit
  • Membrane Proteins
  • Recombinant Proteins
  • Runx2 protein, mouse
  • Smad Proteins
  • neogenin
  • p38 Mitogen-Activated Protein Kinases
  • Bone Morphogenetic Protein Receptors