Oligodendrocyte differentiation and signaling after transferrin internalization: A mechanism of action

• Published in: Experimental neurology 2013-10, Vol.248, p.262-274
• Main Authors: Pérez, María Julia, Fernandez, Natalia, Pasquini, Juana María
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Clathrin - metabolism; Female; Fyn tyrosine kinase; Male; MAP Kinase Signaling System - physiology; Medical sciences; MEK/ERK pathways; Neurology; Neuropharmacology; Oligodendrocyte differentiation and transferrin; Oligodendroglia - cytology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PI3K/Akt pathway; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fyn - metabolism; Rats; Rats, Wistar; Receptors, Transferrin - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Transferrin - metabolism; Transferrin - pharmacology
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2013.06.014

Oligodendrocytes are the cells producing the myelin membrane around the axons in the central nervous system and, although apotransferrin (aTf) is required for oligodendrocyte differentiation, the underlying mechanisms are not fully understood. Fyn tyrosine kinase, a member of the Src family of proteins, has been shown to play an important role in myelination by up-regulating the expression of myelin basic protein; however, a molecular link between aTf and Fyn kinase signaling pathway during oligodendrocytes differentiation has not been established yet. Our aim was to investigate whether Fyn kinase, MEK/ERK and PI3K/Akt signaling pathways are required for aTf-stimulation of oligodendrocyte differentiation and also to determine if the transferrin receptor is involved in these mechanisms. Treatment of primary cultures of oligodendroglial precursor cells with aTf leads to Fyn kinase activation by a mechanism that involves transferrin receptor. In turn, Fyn kinase activation promotes MEK-mediated transient phosphorylation of ERK1/2. On the other hand, transferrin receptor internalization also produces rapid and sustained activation of Akt, which involves phosphatidylinositol 3-kinase (PI3K) activation. Finally, aTf incorporated through clathrin-mediated endocytosis increases myelin basic protein, F3-contactin and β-tubulin through Fyn/MEK/ERK pathways, as well as an activation of the PI3K/Akt pathway. Our results also demonstrate that the activation of the pathways necessary for oligodendroglial precursor cell maturation is dependent on AP2 recruitment onto the plasma membrane for clathrin-mediated endocytosis of transferrin receptor. [Display omitted] •Mechanisms by which aTf promotes oligodendrocyte differentiation•aTf stimulates Fyn/MEK/ERK and PI3K/Akt pathways.•aTf induces the expression of MBP, β-tubulin and F3-contactin proteins.•Signaling pathways depend on Tf receptor internalization by clathrin-coated pits.