Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor

Biochem Biophys Res Commun. 2015 Aug 14;464(1):263-8. doi: 10.1016/j.bbrc.2015.06.140. Epub 2015 Jun 23.

Abstract

Schwann cells (SCs) play an essentially supportive role in the regeneration of injured peripheral nerve system (PNS). As Netrin-1 is crucial for the normal development of nervous system (NS) and can direct the process of damaged PNS regeneration, our study was designed to determine the role of Netrin-1 in RSC96 Schwann cells (an immortalized rat Schwann cell line) proliferation and migration. Our studies demonstrated that Netrin-1 had no effect on RSC96 cells proliferation, while significantly promoted RSC96 cells migration. The Netrin-1-induced RSC96 cells migration was significantly attenuated by inhibition of p38 and PI3K through pretreatment with SB203580 and LY294002 respectively, but not inhibition of MEK1/2 and JNK by U0126-EtOH and SP600125 individually. Treatment with Netrin-1 enhanced the phosphorylation of p38 and Akt. QRT-PCR indicated that Netrin-1 and only its receptors Unc5a, Unc5b and Neogenin were expressed in RSC96 cells, among which Unc5b expressed the most. And UNC5B protein was significantly increased after stimulated by Netrin-1. In conclusion, we show here that Netrin-1-enhanced SCs migration is mediated by activating p38 MAPK and PI3K-Akt signal cascades via receptor UNC5B, which suggests that Netrin-1 could serve as a new therapeutic strategy and has potential application value for PNS regeneration.

Keywords: MAPK; Migration; Netrin-1; PI3K-Akt; Schwann cell; UNC5B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed
  • Cell Movement / drug effects
  • Cell Proliferation
  • Chromones / pharmacology
  • Enzyme Activation / drug effects
  • Gene Expression Regulation
  • Imidazoles / pharmacology
  • Mice
  • Morpholines / pharmacology
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology*
  • Netrin-1
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / agonists
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology
  • Rats
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Schwann Cells / cytology
  • Schwann Cells / drug effects*
  • Schwann Cells / metabolism
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Chromones
  • Imidazoles
  • Morpholines
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridines
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Unc5b protein, rat
  • Netrin-1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580