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

Thumbnail Image
Files
Jecrois (DevCell 2021) NF1 protection Erk glial progenitors.pdf(10.31 MB)
Date
2021-10-25
relationships.isAuthorOfPublication
relationships.isSecondaryAuthorOf
relationships.isDirectorOf
Authors
Emmanuelle S. Jecrois ; Wang Zheng ; Miriam Bornhorst ; Yinghua Li ; Daniel M. Treisman ; Daphine Muguyo ; Sharon Huynh ; Shayne F. Andrew ; Yuan Wang ; Jingwen Jiang ; Brianna R. Pierce ; Hongmei Mao ; Matthew K. Krause ; Austin Friend ; Francisco M. Nadal-Nicolás ; Steven F. Stasheff ; Wei Li ; Hui Zong ; Roger J. Packer ; Yuan Zhu
item.page.secondaryauthor
Facultades de la UMU::Facultad de Medicina
item.page.director
Publisher
Cell Press.
publication.page.editor
publication.page.department
Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica
DOI
doi: 10.1016/j.devcel.2021.08.004.
item.page.type
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.
publication.page.subject
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
item.page.embargo
Collections
Artículos
Ir a Estadísticas