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

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 Nadal-Nicolas; Steven F Stasheff; Wei Li; Hui Zong; Roger J Packer; Yuan Zhu

doi:10.1016/j.devcel.2021.08.004

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

Dev Cell. 2021 Oct 25;56(20):2871-2885.e6. doi: 10.1016/j.devcel.2021.08.004. Epub 2021 Aug 23.

Authors

Emmanuelle S Jecrois¹, Wang Zheng², Miriam Bornhorst³, Yinghua Li², Daniel M Treisman², Daphine Muguyo², Sharon Huynh², Shayne F Andrew², Yuan Wang², Jingwen Jiang², Brianna R Pierce², Hongmei Mao², Matthew K Krause², Austin Friend², Francisco Nadal-Nicolas⁴, Steven F Stasheff⁵, Wei Li⁴, Hui Zong⁶, Roger J Packer⁷, Yuan Zhu⁸

Affiliations

¹ Gilbert 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.
² Gilbert 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.
³ Gilbert 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; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010, USA.
⁴ Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC 20010, USA; Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
⁷ Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC 20010, USA.
⁸ Gilbert 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; GW Cancer Center, George Washington University, Washington, DC 20052. Electronic address: yzhu@childrensnational.org.

PMID: 34428430
DOI: 10.1016/j.devcel.2021.08.004

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.

Keywords: 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); pediatric low-grade glioma; pilocytic astrocytoma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Brain Neoplasms / metabolism
Brain Neoplasms / therapy
Disease Models, Animal
Eye / metabolism
MAP Kinase Signaling System / physiology*
Mice
Neurofibromatosis 1 / metabolism
Neurofibromatosis 1 / pathology
Neurofibromatosis 1 / therapy*
Neuroglia / metabolism
Optic Nerve / pathology
Optic Nerve Glioma / metabolism
Optic Nerve Glioma / pathology
Optic Nerve Glioma / therapy*
Stem Cells / cytology*

Grants and funding

T32 NS076401/NS/NINDS NIH HHS/United States