1. Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors
- Author
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Shayne F. Andrew, Matthew K. Krause, Emmanuelle S. Jecrois, Austin Friend, Jingwen Jiang, Yinghua Li, Yuan Zhu, Daphine Muguyo, Francisco M Nadal-Nicolás, Brianna R. Pierce, Wei Li, Hongmei Mao, Sharon Huynh, Yuan Wang, Steven F Stasheff, Miriam Bornhorst, Roger J. Packer, Daniel M. Treisman, Hui Zong, and Wang Zheng
- Subjects
MAPK/ERK pathway ,Optic Nerve Glioma ,congenital, hereditary, and neonatal diseases and abnormalities ,Neurofibromatosis 1 ,MAP Kinase Signaling System ,Biology ,Eye ,Retinal ganglion ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Animals ,Progenitor cell ,Molecular Biology ,Gliogenesis ,Brain Neoplasms ,MEK inhibitor ,Stem Cells ,Optic Nerve ,Cell Biology ,Neural stem cell ,nervous system diseases ,Cell biology ,Disease Models, Animal ,Apoptosis ,Optic nerve ,Neuroglia ,Developmental Biology - 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.
- Published
- 2021