title: c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling.
abstract: 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.
authors: Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, London, England, UK.
authors: Xavier
authors: X
authors: Fontana
authors: Mariya
authors: M
authors: Hristova
authors: Clive
authors: C
authors: Da Costa
authors: Smriti
authors: S
authors: Patodia
authors: Laura
authors: L
authors: Thei
authors: Milan
authors: M
authors: Makwana
authors: Bradley
authors: B
authors: Spencer-Dene
authors: Morwena
authors: M
authors: Latouche
authors: Rhona
authors: R
authors: Mirsky
authors: Kristjan R
authors: KR
authors: Jessen
authors: Rüdiger
authors: R
authors: Klein
authors: Gennadij
authors: G
authors: Raivich
authors: Axel
authors: A
authors: Behrens
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002470:Cell Survival; D015536:Down-Regulation / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D051379:Mice; D009046:Motor Neurons / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D019899:Paracrine Communication / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012583:Schwann Cells / Q000502:physiology*
chemical_list: C116599:Artn protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D016755:Proto-Oncogene Proteins c-jun