GDNF family ligands activate multiple events during axonal growth in mature sensory neurons

The need for medical treatment of neuronal trauma motivates the search for new agents to stimulate posttraumatic axonal regrowth, as well as improving understanding of signaling cascades regulating this process. GDNF stimulates axonal regeneration in the peripheral nervous system, but little is known about the mechanism of this effect. Neurturin, artemin and persephin are homologs of GDNF, and their impact on axonal regeneration in adults has not been studied yet. Here we show that neurturin, artemin and GDNF, but not persephin, promote axonal initiation in cultured dorsal root ganglion neurons from young adult mice. This effect requires Src-family kinase activity as it was blocked by SU6656. In neurons from GFRalpha2-deficient mice, neurturin does not significantly promote axonal initiation. We also show that neurturin and GDNF induce extensive lamellipodia formation on neuronal somata and growth cones. GDNF, when applied after the time of axonal initiation in culture, also promotes axonal elongation.