Target-derived GFRalpha1 as an Attractive Guidance Signal for Developing Sensory and Sympathetic Axons via Activation of Cdk5

Neuron. 2002 Oct 24;36(3):387-401. doi: 10.1016/s0896-6273(02)01002-4.

Abstract

Immobilized and diffusible molecular cues regulate axon guidance during development. GFRalpha1, a GPI-anchored receptor for GDNF, is expressed as both membrane bound and secreted forms by accessory nerve cells and peripheral targets of developing sensory and sympathetic neurons during the period of target innervation. A relative deficit of GFRalpha1 in developing axons allows exogenous GFRalpha1 to capture GDNF and present it for recognition by axonal c-Ret receptors. Exogenous GFRalpha1 potentiates neurite outgrowth and acts as a long-range directional cue by creating positional information for c-Ret-expressing axons in the presence of a uniform concentration of GDNF. Soluble GFRalpha1 prolongs GDNF-mediated activation of cyclin-dependent kinase 5 (Cdk5), an event required for GFRalpha1-induced neurite outgrowth and axon guidance. Together with GDNF, target-derived GFRalpha1 can function in a non-cell-autonomous fashion as a chemoattractant cue with outgrowth promoting activity for peripheral neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Cell Communication / drug effects
  • Cell Communication / physiology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Chemotaxis / physiology*
  • Chick Embryo
  • Cues
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Drosophila Proteins*
  • Fluorescent Antibody Technique
  • Ganglia, Sympathetic / cytology
  • Ganglia, Sympathetic / embryology*
  • Ganglia, Sympathetic / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Growth Cones / drug effects
  • Growth Cones / metabolism*
  • Growth Cones / ultrastructure
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurites / ultrastructure
  • Neurons, Afferent / cytology
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism*
  • Nodose Ganglion / cytology
  • Nodose Ganglion / embryology*
  • Nodose Ganglion / metabolism
  • Proto-Oncogene Proteins / deficiency*
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • Rats
  • Receptor Protein-Tyrosine Kinases / deficiency*
  • Receptor Protein-Tyrosine Kinases / drug effects
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Brain-Derived Neurotrophic Factor
  • Drosophila Proteins
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, rat
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, rat
  • Cyclin-Dependent Kinases