Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent
Emmanuelle S Jecrois1, Wang Zheng2, Miriam Bornhorst3
1Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC 20010, USA; Center for Neuroscience Research, Children's National Hospital, Washington, DC 20010, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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.
Insights
Pediatric low-grade gliomas (pLGGs) arise from disrupted brain development due to hyperactive Mek-Erk/MAPK signaling. Targeting this pathway in early development can prevent tumor formation and neuronal damage.
Area of Science:
- Neuro-oncology
- Developmental Biology
- Cancer Genetics
Background:
- Pediatric low-grade gliomas (pLGGs) are the most common pediatric brain tumors, but their developmental origins are poorly understood.
- Neurofibromatosis type 1 (NF1) is a genetic disorder associated with an increased risk of pLGGs, particularly in the optic pathway.
Purpose of the Study:
- To elucidate the mechanism of vulnerability leading to NF1-associated optic pathway gliomas (NF1-OPGs) during development.
- To identify potential therapeutic targets for preventing pLGG formation and associated neurological damage.
Main Methods:
- Utilized mouse models of NF1-associated pLGGs (NF1-OPGs).
- Investigated the role of Mek-Erk/MAPK signaling during gliogenesis in specific precursor cell populations.
- Assessed the impact of Nf1 loss on glial progenitor production and differentiation.
- Examined the effects of genetic manipulation (Mek1/Mek2 allele removal) and pharmacological inhibition (MEK inhibitor) on tumor development and neuronal survival.
Main Results:
- NF1-OPGs originate from developmentally transient glial progenitors (GPs) in the optic nerve, not local progenitors.
- Loss of Nf1 leads to hyperactive Erk/MAPK signaling, overproducing GPs by disrupting the balance between stem cell maintenance and gliogenesis in radial glia (RG).
- Persistent RG-like GPs initiate NF1-OPGs and cause retinal ganglion cell apoptosis.
- Reducing Mek1/Mek2 alleles or transient MEK inhibition normalized GP differentiation, preventing NF1-OPG formation and neurodegeneration.
Conclusions:
- Disrupted Mek-Erk/MAPK signaling in specific glial progenitor populations is a key mechanism underlying pLGG development in NF1.
- Targeting Mek-Erk/MAPK signaling offers a potential preventative strategy for pLGGs before irreversible neurological damage occurs.
- This study provides proof-of-concept for early intervention to prevent pediatric brain tumors and associated complications.
