GDNF Acts as a Chemoattractant to Support ephrinA-Induced Repulsion of Limb Motor Axons

SummaryDespite the abundance of guidance cues in vertebrate nervous systems, little is known about cooperation between them [1, 2 and 3]. Motor axons of the lateral motor column (LMCL) [4 and 5] require two ligand/receptor systems, ephrinA/EphA4 and glial cell line-derived neurotrophic factor (GDNF)/Ret, to project to the dorsal limb [6, 7 and 8]. Deletion of either EphA4 or Ret in mice leads to rerouting of a portion of LMCL axons to the ventral limb, a phenotype enhanced in EphA4;Ret double mutants [ 7 and 8]. The guidance errors in EphA4 knockouts were attributed to the lack of repulsion from ephrinAs in the ventral mesenchyme [ 6, 7 and 9]. However, it has remained unclear how GDNF, expressed dorsally next to the choice point [8], acts on motor axons and cooperates with ephrinAs. Here we show that GDNF induces attractive turning of LMCL 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.

Graphical AbstractFigure optionsDownload high-quality image (188 K)Download as PowerPoint slideHighlights
► GDNF induces attractive turning of LMCL motor axons via the Ret receptor
► When presented in countergradients, GDNF and ephrinAs cooperate in axon turning
► GDNF has permissive effects and reduces ephrinA-induced collapse and retraction
► First example of two opposing cues promoting the same trajectory choice