Notch1 signaling regulates remyelination in the adult central nervous system

• Published in: Multiple sclerosis 2008-09, Vol.14, p.S25-S25
• Main Authors: Zhang, Y, Argaw, A T, Snyder, B J, Ge, C, Rowitch, D H, Raine, C S, Brosnan, C F, John, G
• Format: Article
• Language: English
• ISSN: 1352-4585

Background: Notch1 and its ligand, Jagged1, have been shown to be expressed in active multiple sclerosis (MS) lesions. During development, activation of Notch signaling regulates oligodendrocyte differentiation and myelin formation, but whether Notch regulates remyelination in the adult remains unresolved. Objective: To address this question directly, we targeted Notch1 inactivation to early oligodendrocyte progenitor cells (OPC) using Olig1Cre and a new floxed Notch1 allele (Notch1 super(12f)). Methods: Myelin formation and remyelination in Olig1Cre:Notch1 super(12f/12f) mice were compared with littermate controls of relevant genotypes. Results: As expected, during development differentiation of oligodendrocytes was accelerated. More importantly, in adults, resolution of focal demyelinating lesions and remyelination were potentiated, whereas OPC proliferation was restricted. Studies in vitro confirmed that Notch1 signaling promoted OPC proliferation but restricted differentiation and myelin formation. They also revealed that astrocytes exposed to TGF beta 1 restricted OPC maturation via Jagged1-Notch1 signaling. Conclusions: Thus, in MS, Notch1 may represent a potential therapeutic avenue for remyelination by manipulating the size and differentiation state of OPCs, with Notch1 signaling favoring expansion of the OPC pool.