López-Juárez Alejandro, Titus Haley E, Silbak Sadiq H, Pressler Joshua W, Rizvi Tilat A, Bogard Madeleine, Bennett Michael R, Ciraolo Georgianne, Williams Michael T, Vorhees Charles V, Ratner Nancy
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
Division of Pathology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
Cell Rep. 2017 Apr 18;19(3):545-557. doi: 10.1016/j.celrep.2017.03.073.
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.
RAS 病相关的 1 型神经纤维瘤病（NF1）是最常见的常染色体显性遗传病之一。在 NF1 患者中，神经问题可能源于髓磷脂受损，而神经纤维瘤蛋白基因（Nf1）发生突变的小鼠表现出包括髓鞘结构松散在内的白质（WM）缺陷。通过小鼠遗传学研究，我们发现成熟少突胶质细胞中 Nf1 基因剂量的改变会导致渐进性的髓鞘缺陷和由异常 Notch 激活介导的行为异常。阻断 Notch、上游丝裂原活化蛋白激酶（MAPK）或一氧化氮信号通路可挽救半合子 Nf1 突变体中的髓鞘缺陷，而药理学上的γ-分泌酶抑制可挽救异常行为，且对野生型（WT）小鼠无影响。同时抑制相关通路可挽救纯合突变体中的髓鞘异常。在 Nf1 小鼠大脑中也观察到 Notch 激活，并且 NF1 患者白质中含有活性 Notch 的细胞增多。因此，我们确定 Notch 是一种在 RAS 病中调节髓鞘结构和行为的 Nf1 效应因子，并表明抑制 Notch 信号通路可能是 NF1 的一种治疗策略。
