Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb

Neuron. 2006 Apr 6;50(1):35-47. doi: 10.1016/j.neuron.2006.02.020.


Establishment of limb innervation by motor neurons involves a series of hierarchical axon guidance decisions by which motor-neuron subtypes evaluate peripheral guidance cues and choose their axonal trajectory. Earlier work indicated that the pathway into the dorsal limb by lateral motor column (LMC[l]) axons requires the EphA4 receptor, which mediates repulsion elicited by ephrinAs expressed in ventral limb mesoderm. Here, we implicate glial-cell-line-derived neurotrophic factor (GDNF) and its receptor, Ret, in the same guidance decision. In Gdnf or Ret mutant mice, LMC(l) axons follow an aberrant ventral trajectory away from dorsal territory enriched in GDNF, showing that the GDNF/Ret system functions as an instructive guidance signal for motor axons. This phenotype is enhanced in mutant mice lacking Ret and EphA4. Thus, Ret and EphA4 signals cooperate to enforce the precision of the same binary choice in motor-axon guidance.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / physiology*
  • Blotting, Western / methods
  • Body Patterning / physiology
  • Chick Embryo
  • Efferent Pathways* / embryology
  • Efferent Pathways* / metabolism
  • Electroporation / methods
  • Embryo, Mammalian
  • Extremities* / embryology
  • Extremities* / growth & development
  • Extremities* / innervation
  • Gene Expression Regulation, Developmental / physiology
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / physiology*
  • Green Fluorescent Proteins / metabolism
  • Immunohistochemistry / methods
  • Mice
  • Mice, Transgenic
  • Motor Neurons / cytology*
  • Mutation / genetics
  • Neurofilament Proteins / metabolism
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / physiology
  • Receptor, EphA4 / genetics
  • Receptor, EphA4 / physiology*
  • Signal Transduction / physiology*
  • Spinal Cord / embryology
  • Spinal Cord / growth & development
  • Spinal Cord / metabolism


  • Glial Cell Line-Derived Neurotrophic Factor
  • Neurofilament Proteins
  • Green Fluorescent Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor, EphA4
  • Ret protein, mouse