Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior

SUMMARY The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1+/− mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1.
In Brief López-Juárez et al. find that loss of the RAS-GTP regulator Nf1 in oligodendrocytes leads to myelin and behavioral defects mediated by hyperactive Notch and upstream pathways. Pharmacological inhibition of Notch signaling rescues aberrant behavior in Nf1 mutant mice and may improve neurological manifestations in neurofibromatosis type 1 patients.