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Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors

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Jecrois (DevCell 2021) NF1 protection Erk glial progenitors.pdf(10.31 MB)
Date
2021-10-25
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Authors
Jecrois, Emmanuelle S. ; Zheng, Wang ; Bornhorst, Miriam ; Li, Yinghua ; Treisman, Daniel M. ; Muguyo, Daphine ; Huynh, Sharon ; Andrew, Shayne F. ; Wang, Yuan ; Jiang, Jingwen ; Pierce, Brianna R. ; Mao, Hongmei ; Krause, Matthew K. ; Friend, Austin ; Steven F. Stasheff ; Li, Wei ; Zong, Hui ; Packer, Roger J. ; Zhu, Yuan ; Nadal-Nicolás, Francisco Manuel
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Facultad de Medicina
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Publisher
Cell Press
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Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica
DOI
https://doi.org/10.1016/j.devcel.2021.08.004
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info:eu-repo/semantics/article
Description
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.
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NF1 , Neurofibromatosis type 1 , hMZ-RG , hVZ-RG , Hypothalamic mantle zone radial glia , Hypothalamic ventricular zone radial glia , Neural stem cells , Optic pathway glioma (OPG) , Pilocytic astrocytoma , Pediatric low-grade glioma
Citation
Dev Cell. 2021 Oct 25;56(20):2871-2885.e6
URI
http://hdl.handle.net/10201/195451
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