title: The transcription factor serum response factor stimulates axon regeneration through cytoplasmic localization and cofilin interaction.
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.
authors.affiliation: 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.
authors.forename: Sina
authors.initials: S
authors.lastname: Stern
authors.forename: Stephanie
authors.initials: S
authors.lastname: Haverkamp
authors.forename: Daniela
authors.initials: D
authors.lastname: Sinske
authors.forename: Andrea
authors.initials: A
authors.lastname: Tedeschi
authors.forename: Ulrike
authors.initials: U
authors.lastname: Naumann
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.forename: Bernd
authors.initials: B
authors.lastname: Knöll
mesh_terms: D051339:Actin Depolymerizing Factors / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects*; D019771:Axotomy; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D005154:Facial Nerve / Q000502:physiology; D005260:Female; D049452:Green Fluorescent Proteins; D008297:Male; D051379:Mice; D009416:Nerve Regeneration / Q000187:drug effects*; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D026362:Serum Response Factor / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D026362:Serum Response Factor; D049452:Green Fluorescent Proteins