期刊
DEVELOPMENTAL CELL
卷 56, 期 20, 页码 2871-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2021.08.004
关键词
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资金
- DOD NFRP [W81XWH1810685]
- NIH Neuroscience training grant [T32-NS076401]
- Francis S. Collins Neurofibromatosis Therapeutic Association Program
- Hyundai Hope On Wheels Young Investigator Award
- National Science Foundation Graduate Research Fellowship Program
- U.S. Department of Defense (DOD) [W81XWH1810685] Funding Source: U.S. Department of Defense (DOD)
NF1-OPGs arise from vulnerability to Mek-Erk/MAPK signaling dependency during gliogenesis, caused by disruption of the balance between stem-cell maintenance and gliogenesis in brain-derived migrating glial progenitors. Removal of specific genes or transient treatment with a low-dose MEK inhibitor can prevent NF1-OPG formation and neuronal degeneration.
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. Weprovide the proof-of-concept evidence for preventing pLGGs before tumor-associated neurological damage enters an irreversible phase.
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