The AP-1 transcription factor c-Jun is a master regulator of the axonal response 
in neurons. c-Jun also functions as a negative regulator of myelination in 
Schwann cells (SCs) and is strongly reactivated in SCs upon axonal injury. We 
demonstrate here that, after injury, the absence of c-Jun specifically in SCs 
caused impaired axonal regeneration and severely increased neuronal cell death. 
c-Jun deficiency resulted in decreased expression of several neurotrophic 
factors, and GDNF and Artemin, both of which encode ligands for the Ret receptor 
tyrosine kinase, were identified as novel direct c-Jun target genes. Genetic 
inactivation of Ret specifically in neurons resulted in regeneration defects 
without affecting motoneuron survival and, conversely, administration of 
recombinant GDNF and Artemin protein substantially ameliorated impaired 
regeneration caused by c-Jun deficiency. These results reveal an unexpected 
function for c-Jun in SCs in response to axonal injury, and identify paracrine 
Ret signaling as an important mediator of c-Jun function in SCs during 
regeneration.