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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / physiology*
  • Actins / metabolism
  • Animals
  • Axons / drug effects*
  • Axotomy
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism*
  • Facial Nerve / physiology
  • Female
  • Green Fluorescent Proteins
  • Male
  • Mice
  • Nerve Regeneration / drug effects*
  • Peripheral Nerves / cytology
  • Peripheral Nerves / drug effects
  • Phosphorylation
  • Polymerase Chain Reaction
  • Serum Response Factor / pharmacology*
  • Subcellular Fractions / metabolism


  • Actin Depolymerizing Factors
  • Actins
  • Serum Response Factor
  • Green Fluorescent Proteins