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

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. [Display omitted] •Migrating GPs, not local APCs, are Mek/Erk dependent and thus susceptible to Nf1 loss•Nf1 is required to maintain the balance between stem-cell maintenance and gliogenesis•Partial Mek loss normalizes differentiation of Nf1−/− migrating GPs and prevents NF1-OPG•Transient neonatal low-dose MEKi treatment prevents NF1-OPG and neuronal degeneration The mechanism of vulnerability to pediatric low-grade gliomas during development remains unknown. Jecrois et al. demonstrate that NF1-OPG arise from the dependency of Mek-Erk/MAPK signaling during gliogenesis of developmentally transient migrating progenitors in the optic nerve. Transient post-natal treatment with a MEK inhibitor prevents NF1-OPG formation and retinal neuronal degeneration.