GDNF acts as a chemoattractant to support ephrinA-induced repulsion of limb motor axons.
Despite the abundance of guidance cues in vertebrate nervous systems, little is known about cooperation between them. Motor axons of the lateral motor column (LMC(L)) require two ligand/receptor systems, ephrinA/EphA4 and glial cell line-derived neurotrophic factor (GDNF)/Ret, to project to the dorsal limb. Deletion of either EphA4 or Ret in mice leads to rerouting of a portion of LMC(L) axons to the ventral limb, a phenotype enhanced in EphA4;Ret double mutants. The guidance errors in EphA4 knockouts were attributed to the lack of repulsion from ephrinAs in the ventral mesenchyme. However, it has remained unclear how GDNF, expressed dorsally next to the choice point, acts on motor axons and cooperates with ephrinAs. Here we show that GDNF induces attractive turning of LMC(L) axons. When presented in countergradients, GDNF and ephrinAs cooperate in axon turning, indicating that the receptors Ret and EphA4 invoke opposite effects within the same growth cone. GDNF also acts in a permissive manner by reducing ephrinA-induced collapse and keeping the axons in a growth-competent state. This is the first example of two opposing cues promoting the same trajectory choice at an intermediate target.
Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, Martinsried D-82152, Germany.
Irina
I
Dudanova
Graziana
G
Gatto
Rüdiger
R
Klein
D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D036342:Ephrins / Q000235:genetics / Q000378:metabolism*; D005121:Extremities / Q000294:innervation*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology* / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
D002630:Chemotactic Factors; D036342:Ephrins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020033:Protein Isoforms