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Open Biol. 2016 Aug;6(8). pii: 160091. doi: 10.1098/rsob.160091.

Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury.

Author information

1
Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
2
Department of Neurosurgery, Bezirkskrankenhaus Günzburg, Ulm University, 89081 Ulm, Germany.
3
Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany bernd.knoell@uni-ulm.de.

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.

KEYWORDS:

ATF3; RAG; axon regeneration; facial nerve; neuropeptide

PMID:
27581653
PMCID:
PMC5008009
DOI:
10.1098/rsob.160091
[Indexed for MEDLINE]
Free PMC Article

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