The mechanism of vulnerability to pediatric low-grade gliomas (pLGGs)—the most common brain tumor in children—during development remains largely unknown. Using mouse models of neurofibromatosis type 1 (NF1)-associated pLGGs in the optic pathway (NF1-OPG), we demonstrate that NF1-OPG arose from the vulnerability to the dependency of Mek-Erk/MAPK signaling during gliogenesis of one of the two developmentally transient precursor populations in the optic nerve, brain-derived migrating glial progenitors (GPs), but not local progenitors. Hyperactive Erk/MAPK signaling by Nf1 loss overproduced GPs by disrupting the balance between stem-cell maintenance and gliogenesis of hypothalamic ventricular zone radial glia (RG). Persistence of RG-like GPs initiated NF1-OPG, causing Bax-dependent apoptosis in retinal ganglion cells. Removal of three Mek1/Mek2 alleles or transient post-natal treatment with a low-dose MEK inhibitor normalized differentiation of Nf1^−/− RG-like GPs, preventing NF1-OPG formation and neuronal degeneration. We provide the proof-of-concept evidence for preventing pLGGs before tumor-associated neurological damage enters an irreversible phase.

儿童低级别胶质瘤（pLGGs）——儿童最常见的脑肿瘤——在发育过程中的易感性机制在很大程度上仍然未知。使用视神经通路 (NF1-OPG) 中 1 型神经纤维瘤病 (NF1) 相关 pLGG 的小鼠模型，我们证明 NF1-OPG 是由于在两者之一的胶质生成过程中对 Mek-Erk/MAPK 信号的依赖性的脆弱性引起的视神经中发育短暂的前体种群，脑源性迁移神经胶质祖细胞（GPs），但不是局部祖细胞。Nf1过度活跃的 Erk/MAPK 信号损失通过破坏干细胞维持和下丘脑室区径向胶质细胞 (RG) 的胶质生成之间的平衡而过度产生 GP。RG 样 GP 的持续存在启动了 NF1-OPG，导致视网膜神经节细胞中 Bax 依赖性细胞凋亡。去除三个Mek1 / Mek2等位基因或使用低剂量 MEK 抑制剂进行短暂的产后治疗使Nf1 ^-/- RG 样 GP 的分化正常化，防止 NF1-OPG 形成和神经元变性。我们提供了在肿瘤相关神经损伤进入不可逆阶段之前预防 pLGG 的概念验证证据。