Journal
JOURNAL OF CELL BIOLOGY
Volume 198, Issue 1, Pages 127-141Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201205025
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Funding
- Marie Curie Intraeuropean Fellowship [PIEF-GA-2009-236307]
- Cancer Research UK
- BBSRC [S20299, B/D009537/1]
- Wellcome Research Trust [WT088646MA]
- SPARKS Medical
- Biotechnology and Biological Sciences Research Council [S20299] Funding Source: researchfish
- Cancer Research UK [15679] Funding Source: researchfish
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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.
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