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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Transformed
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Cell Movement / drug effects
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Cell Proliferation
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Chromones / pharmacology
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Enzyme Activation / drug effects
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Gene Expression Regulation
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Imidazoles / pharmacology
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Mice
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Morpholines / pharmacology
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Nerve Growth Factors / pharmacology*
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Netrin-1
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / agonists
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / pharmacology
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Rats
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Receptors, Cell Surface / agonists
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Schwann Cells / cytology
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Schwann Cells / drug effects*
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Schwann Cells / metabolism
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Signal Transduction
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / pharmacology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Chromones
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Imidazoles
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Morpholines
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Nerve Growth Factors
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Ntn1 protein, mouse
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Ntn1 protein, rat
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridines
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Receptors, Cell Surface
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Recombinant Proteins
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Tumor Suppressor Proteins
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Unc5b protein, rat
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Netrin-1
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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SB 203580