Genetic epistasis between heparan sulfate and FGF-Ras signaling controls lens development

Dev Biol. 2011 Jul 1;355(1):12-20. doi: 10.1016/j.ydbio.2011.04.007. Epub 2011 Apr 17.

Abstract

Vertebrate lens development depends on a complex network of signaling molecules to coordinate cell proliferation, migration and differentiation. In this study, we have investigated the role of heparan sulfate in lens specific signaling by generating a conditional ablation of heparan sulfate modification genes, Ndst1 and Ndst2. In this mutant, N-sulfation of heparan sulfate was disrupted after the lens induction stage, resulting in reduced lens cell proliferation, increased cell death and defective lens fiber differentiation in later lens development. The loss of Ndst function also prevented the assembly of Fgf/Fgfr complexes on the lens cell surface and disrupted ERK signaling within the lens. We further demonstrated that Ndst mutation completely inhibited the FGF1 and Fgf3 overexpression phenotypes, but Kras reactivation was sufficient to reverse the Ndst deficient lens differentiation defect. The epistatic relationship between Ndst and FGF-Ras signaling demonstrates that FGF signaling is the predominant signaling pathway controlled by Ndst in lens development.

Publication types

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

MeSH terms

  • Amidohydrolases / genetics
  • Amidohydrolases / metabolism*
  • Animals
  • Cell Death
  • Cell Differentiation
  • Cell Proliferation
  • Epistasis, Genetic*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Fibroblast Growth Factors / genetics*
  • Heparitin Sulfate / genetics*
  • Lens, Crystalline / enzymology
  • Lens, Crystalline / growth & development*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism*
  • ras Proteins / genetics*

Substances

  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factors
  • Heparitin Sulfate
  • Extracellular Signal-Regulated MAP Kinases
  • Ndst2 protein, mouse
  • Sulfotransferases
  • heparitin sulfotransferase
  • Amidohydrolases
  • ras Proteins