Neurotrophin-3 targets the translational initiation machinery in oligodendrocytes

• Published in: Glia 2009-12, Vol.57 (16), p.1754-1764
• Main Authors: Coelho, Rochelle P., Yuelling, Larra M., Fuss, Babette, Sato-Bigbee, Carmen
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Blotting, Western; Cell Differentiation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Myelin Basic Protein - genetics; Myelin Basic Protein - metabolism; Myelin Proteins; Myelin Sheath - drug effects; Myelin Sheath - genetics; Myelin Sheath - metabolism; Myelin-Associated Glycoprotein - genetics; Myelin-Associated Glycoprotein - metabolism; Myelin-Oligodendrocyte Glycoprotein; myelination; Neurotrophin 3 - metabolism; Neurotrophin 3 - pharmacology; neurotrophin-3; oligodendrocytes; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Protein Biosynthesis - drug effects; Protein Biosynthesis - genetics; Protein Biosynthesis - physiology; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; translational regulation
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.20888

Neurotrophin‐3 (NT‐3) regulates oligodendrocyte (OLG) differentiation by mechanisms that remain poorly understood. Exposure of OLGs to NT‐3 induces a significant increase in the levels of myelin basic protein (MBP). However, we found that this stimulation occurs in the absence of measurable effects on MBP gene promoter activation or mRNA expression, suggesting that NT‐3 upregulates MBP protein expression by a posttranscriptional mechanism. Furthermore, NT‐3 also causes an increase in the levels of myelin‐associated glycoprotein (MAG) and myelin OLG glycoprotein (MOG), raising the possibility of a more general effect on myelin protein synthesis. Surprisingly, 35S‐methionine incorporation into total OLG proteins demonstrated a 50% increase in labeling following only a brief, 15‐min treatment with NT‐3. Such a remarkably fast response is unlikely due to transcriptional activation, reinforcing the possibility that NT‐3 may play a crucial role in regulating protein expression by a posttranscriptional mechanism. In support of this idea, we found that NT‐3 stimulates the phosphorylation of essential regulators of the initiation machinery, eukaryotic initiation factor 4E (eIF4E), and its inhibitory binding partner 4E binding protein 1 (4EBP1), two crucial players in controlling cap‐dependent protein synthesis. This stimulation involves the activation of pathways mediated by ERK1/2 and PI3K/mTOR, implicating these two kinase systems as modulators of protein synthesis in developing OLGs. Altogether, these observations show for the first time that NT‐3 has the capacity of targeting the translational machinery and suggest a potential stimulatory effect of this neurotrophin on myelination by direct action on protein translation in the OLGs. © 2009 Wiley‐Liss, Inc.