title: CNS axon regeneration inhibitors stimulate an immediate early gene response via MAP kinase-SRF signaling.
abstract: BACKGROUND
  CNS axon regeneration inhibitors such as Nogo and CSPGs (Chondroitin Sulfate Proteoglycans) are major extrinsic factors limiting outgrowth of severed nerve fibers. However, knowledge on intracellular signaling cascades and gene expression programs activated by these inhibitors in neurons is sparse. Herein we studied intracellular signaling cascades activated by total myelin, Nogo and CSPGs in primary mouse CNS neurons.
  
  
  RESULTS
  Total myelin, Nogo and CSPGs stimulated gene expression activity of the serum response factor (SRF), a central gene regulator of immediate early (IEG) and actin cytoskeletal gene transcription. As demonstrated by pharmacological interference, SRF-mediated IEG activation by myelin, Nogo or CSPGs depended on MAP kinase, to a lesser extent on Rho-GTPase but not on PKA signaling. Stimulation of neurons with all three axon growth inhibitors activated the MAP kinase ERK. In addition to ERK activation, myelin activated the IEG c-Fos, an important checkpoint of neuronal survival vs. apoptosis. Employing Srf deficient neurons revealed that myelin-induced IEG activation requires SRF. This suggests an SRF function in mediating neuronal signaling evoked by axon regeneration associated inhibitors. Besides being a signaling target of axon growth inhibitors, we show that constitutively-active SRF-VP16 can be employed to circumvent neurite growth inhibition imposed by myelin, Nogo and CSPGs.
  
  
  CONCLUSIONS
  In sum, our data demonstrate that axon regeneration inhibitors such as Nogo trigger gene expression programs including an SRF-dependent IEG response via MAP kinases and Rho-GTPases.
authors.affiliation: Department Molecular Biology, Eberhard-Karls-University Tübingen, Interfaculty Institute for Cell Biology, Auf der Morgenstelle 15, 72076, Tübingen, Germany. sina.stern@dzne.de.|Current address: German Centre for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. sina.stern@dzne.de.
authors.forename: Sina
authors.initials: S
authors.lastname: Stern
authors.affiliation: Department Molecular Biology, Eberhard-Karls-University Tübingen, Interfaculty Institute for Cell Biology, Auf der Morgenstelle 15, 72076, Tübingen, Germany. bernd.knoell@uni-ulm.de.|Current address: Ulm University, Institute for Physiological Chemistry, 89081, Ulm, Germany. bernd.knoell@uni-ulm.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Knöll
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002490:Central Nervous System / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017781:Genes, Immediate-Early; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D009185:Myelin Proteins / Q000494:pharmacology; D009186:Myelin Sheath / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D000070798:Nogo Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D009185:Myelin Proteins; D000070798:Nogo Proteins; D016760:Proto-Oncogene Proteins c-fos; C000603201:Rtn4 protein, mouse; D026362:Serum Response Factor; D048049:Extracellular Signal-Regulated MAP Kinases