Ret is a multifunctional coreceptor that integrates diffusible- and contact-axon guidance signals

Cell. 2012 Feb 3;148(3):568-82. doi: 10.1016/j.cell.2012.01.024.


Growing axons encounter multiple guidance cues, but it is unclear how separate signals are resolved and integrated into coherent instructions for growth cone navigation. We report that glycosylphosphatidylinositol (GPI)-anchored ephrin-As function as "reverse" signaling receptors for motor axons when contacted by transmembrane EphAs present in the dorsal limb. Ephrin-A receptors are thought to depend on transmembrane coreceptors for transmitting signals intracellularly. We show that the receptor tyrosine kinase Ret is required for motor axon attraction mediated by ephrin-A reverse signaling. Ret also mediates GPI-anchored GFRα1 signaling in response to GDNF, a diffusible chemoattractant in the limb, indicating that Ret is a multifunctional coreceptor for guidance molecules. Axons respond synergistically to coactivation by GDNF and EphA ligands, and these cooperative interactions are gated by GFRα1 levels. Our studies uncover a hierarchical GPI-receptor signaling network that is constructed from combinatorial components and integrated through Ret using ligand coincidence detection.

Publication types

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

MeSH terms

  • Animals
  • Axons / metabolism*
  • Chick Embryo
  • Embryo, Mammalian / metabolism
  • Ephrins / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Mice
  • Motor Neurons / metabolism
  • Proto-Oncogene Proteins c-ret / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • Ephrins
  • Gfra1 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse