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J Neurosci. 2013 Nov 27;33(48):18836-48. doi: 10.1523/JNEUROSCI.3029-13.2013.

The transcription factor serum response factor stimulates axon regeneration through cytoplasmic localization and cofilin interaction.

Author information

1
Neuronal Gene Expression Laboratory and Molecular Organ Function Laboratory, Eberhard Karls University Tübingen, Interfaculty Institute for Cell Biology, Department of Molecular Biology, 72076 Tübingen, Germany; Laboratory for NeuroRegeneration and Repair and Laboratory for Molecular Neuro-Oncology, Eberhard Karls University Tübingen, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany; and Department of Gene Therapy and Institute for Physiological Chemistry, Ulm University, 89081 Ulm, Germany.

Abstract

Axonal injury generates growth inert retraction bulbs with dynamic cytoskeletal properties that are severely compromised. Conversion of "frozen" retraction bulbs into actively progressing growth cones is a major aim in axon regeneration. Here we report that murine serum response factor (SRF), a gene regulator linked to the actin cytoskeleton, modulates growth cone actin dynamics during axon regeneration. In regeneration-competent facial motoneurons, Srf deletion inhibited axonal regeneration. In wild-type mice after nerve injury, SRF translocated from the nucleus to the cytoplasm, suggesting a cytoplasmic SRF function in axonal regeneration. Indeed, adenoviral overexpression of cytoplasmic SRF (SRF-ΔNLS-GFP) stimulated axonal sprouting and facial nerve regeneration in vivo. In primary central and peripheral neurons, SRF-ΔNLS-GFP stimulated neurite outgrowth, branch formation, and growth cone morphology. Furthermore, we uncovered a link between SRF and the actin-severing factor cofilin during axonal regeneration in vivo. Facial nerve axotomy increased the total cofilin abundance and also nuclear localization of phosphorylated cofilin in a subpopulation of lesioned motoneurons. This cytoplasmic-to-nucleus translocation of P-cofilin upon axotomy was reduced in motoneurons expressing SRF-ΔNLS-GFP. Finally, we demonstrate that cytoplasmic SRF and cofilin formed a reciprocal regulatory unit. Overexpression of cytoplasmic SRF reduced cofilin phosphorylation and vice versa: overexpression of cofilin inhibited SRF phosphorylation. Therefore, a regulatory loop consisting of SRF and cofilin might take part in reactivating actin dynamics in growth-inert retraction bulbs and facilitating axon regeneration.

PMID:
24285890
DOI:
10.1523/JNEUROSCI.3029-13.2013
[Indexed for MEDLINE]
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