Abstract
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.