FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion

Nat Genet. 2009 Mar;41(3):289-98. doi: 10.1038/ng.316. Epub 2009 Feb 15.

Abstract

The spontaneous dominant mouse mutant, Elbow knee synostosis (Eks), shows elbow and knee joint synosotsis, and premature fusion of cranial sutures. Here we identify a missense mutation in the Fgf9 gene that is responsible for the Eks mutation. Through investigation of the pathogenic mechanisms of joint and suture synostosis in Eks mice, we identify a key molecular mechanism that regulates FGF9 signaling in developing tissues. We show that the Eks mutation prevents homodimerization of the FGF9 protein and that monomeric FGF9 binds to heparin with a lower affinity than dimeric FGF9. These biochemical defects result in increased diffusion of the altered FGF9 protein (FGF9(Eks)) through developing tissues, leading to ectopic FGF9 signaling and repression of joint and suture development. We propose a mechanism in which the range of FGF9 signaling in developing tissues is limited by its ability to homodimerize and its affinity for extracellular matrix heparan sulfate proteoglycans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Mutational Analysis
  • Diffusion
  • Extracellular Matrix / metabolism*
  • Fibroblast Growth Factor 9 / genetics
  • Fibroblast Growth Factor 9 / metabolism*
  • Heparan Sulfate Proteoglycans / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation, Missense / physiology
  • Protein Binding
  • Protein Multimerization / genetics
  • Protein Multimerization / physiology*
  • Protein Transport / genetics
  • Protein Transport / physiology
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Synostosis / genetics
  • Tissue Distribution

Substances

  • Fgf9 protein, mouse
  • Fibroblast Growth Factor 9
  • Heparan Sulfate Proteoglycans