Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination.
In the developing CNS, Notch1 and its ligand, Jagged1, regulate oligodendrocyte differentiation and myelin formation, but their role in repair of demyelinating lesions in diseases such as multiple sclerosis remains unresolved. To address this question, we generated a mouse model in which we targeted Notch1 inactivation to oligodendrocyte progenitor cells (OPCs) using Olig1Cre and a floxed Notch1 allele, Notch1(12f). During CNS development, OPC differentiation was potentiated in Olig1Cre:Notch1(12f/12f) mice. Importantly, in adults, remyelination of demyelinating lesions was also accelerated, at the expense of proliferation within the progenitor population. Experiments in vitro confirmed that Notch1 signaling was permissive for OPC expansion but inhibited differentiation and myelin formation. These studies also revealed that astrocytes exposed to TGF-beta1 restricted OPC maturation via Jagged1-Notch1 signaling. These data suggest that Notch1 signaling is one of the mechanisms regulating OPC differentiation during CNS remyelination. Thus, Notch1 may represent a potential therapeutical avenue for lesion repair in demyelinating disease.
Zhang
Yueting
Y
Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Argaw
Azeb Tadesse
AT
Gurfein
Blake T
BT
Zameer
Andleeb
A
Snyder
Brian J
BJ
Ge
Changhui
C
Lu
Q Richard
QR
Rowitch
David H
DH
Raine
Cedric S
CS
Brosnan
Celia F
CF
John
Gareth R
GR
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009186:Myelin Sheath / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins