Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Cell Rep. 2013 Sep 26;4(6):1197-212. doi: 10.1016/j.celrep.2013.08.011. Epub 2013 Sep 12.
Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1-NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.
患有神经纤维瘤病 1 型 (NF1) 和 Costello 综合征 Rasopathy 的患者存在行为缺陷。在 NF1 患者中，这些缺陷可能与白质扩大和异常髓鞘有关。为了模拟这些特征，我们在小鼠少突胶质细胞中诱导 Nf1 缺失或 HRas 过度激活。大脑白质束的扩大与髓鞘松解、紧密连接蛋白 11 的下调以及连接蛋白 32 的定位错误有关。令人惊讶的是，血管周星形胶质细胞和血脑屏障 (BBB) 出现了非细胞自主缺陷，暗示存在可溶性介质。一氧化氮 (NO) 可以破坏紧密连接和缝隙连接，突变白质中 NO 和 NO 合酶 (NOS1-NOS3) 上调。用一氧化氮合酶抑制剂 NG-硝基-L-精氨酸甲酯或抗氧化剂 N-乙酰半胱氨酸治疗小鼠可以纠正细胞表型。CNP-HRasG12V 小鼠也表现出运动过度活跃，抗氧化剂治疗可以挽救这种现象。我们得出结论，Nf1/Ras 调节少突胶质细胞中的 NOS，而异常的 NO 信号转导可以改变周围的血管。这些数据表明，抗氧化剂可能改善 Rasopathy 患者的一些行为缺陷。
