1. Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors.
- Author
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Jecrois ES, Zheng W, Bornhorst M, Li Y, Treisman DM, Muguyo D, Huynh S, Andrew SF, Wang Y, Jiang J, Pierce BR, Mao H, Krause MK, Friend A, Nadal-Nicolas F, Stasheff SF, Li W, Zong H, Packer RJ, and Zhu Y
- Subjects
- Animals, Brain Neoplasms metabolism, Brain Neoplasms therapy, Disease Models, Animal, Eye metabolism, Mice, Neurofibromatosis 1 metabolism, Neurofibromatosis 1 pathology, Neuroglia metabolism, Optic Nerve pathology, Optic Nerve Glioma metabolism, Optic Nerve Glioma pathology, MAP Kinase Signaling System physiology, Neurofibromatosis 1 therapy, Optic Nerve Glioma therapy, Stem Cells cytology
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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