title: Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury.
abstract: Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce 'effector' RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types.
authors: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Manuel
authors: M
authors: Gey
authors: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Renate
authors: R
authors: Wanner
authors: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Corinna
authors: C
authors: Schilling
authors: Department of Neurosurgery, Bezirkskrankenhaus Günzburg, Ulm University, 89081 Ulm, Germany.
authors: Maria T
authors: MT
authors: Pedro
authors: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Daniela
authors: D
authors: Sinske
authors: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany bernd.knoell@uni-ulm.de.
authors: Bernd
authors: 0000-0001-7685-3796
authors: B
authors: Knöll
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics*; D000818:Animals; D001369:Axons / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D051379:Mice; D009154:Mutation; D020932:Nerve Growth Factor / Q000235:genetics; D009416:Nerve Regeneration; D009479:Neuropeptides / Q000235:genetics*; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000473:pathology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics
chemical_list: C495401:ADCYAP1 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C502240:NGF protein, human; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D020932:Nerve Growth Factor
keywords: ATF3; RAG; axon regeneration; facial nerve; neuropeptide