Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin

J Cell Biol. 2011 Jan 10;192(1):153-69. doi: 10.1083/jcb.201009136. Epub 2011 Jan 3.

Abstract

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson's disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL-syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3-dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid-releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / drug effects
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Embryo, Mammalian / cytology
  • Enzyme Activation / drug effects
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology
  • Heparin / metabolism
  • Humans
  • Immobilized Proteins / metabolism
  • Interneurons / cytology
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Ligands
  • Mice
  • Models, Biological
  • Nerve Tissue Proteins / metabolism*
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurturin / metabolism*
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Rats
  • Signal Transduction / drug effects
  • Syndecan-3 / metabolism*
  • src-Family Kinases / metabolism

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Immobilized Proteins
  • Ligands
  • Nerve Tissue Proteins
  • Neurturin
  • Syndecan-3
  • Heparin
  • src-Family Kinases