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

Aug 26, 2021

Contributor: 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

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.
Copyright © 2021 Elsevier Inc. All rights reserved.

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About The Expert

Emmanuelle S Jecrois

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.

Wang Zheng

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.

Miriam Bornhorst

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.

Yinghua Li

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.

Daniel M Treisman

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.

Daphine Muguyo

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.

Sharon Huynh

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.

Shayne F Andrew

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.

Yuan Wang

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.

Jingwen Jiang

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.

Brianna R Pierce

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.

Hongmei Mao

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.

Matthew K Krause

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.

Austin Friend

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.

Francisco Nadal-Nicolas

Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Steven F Stasheff

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.

Wei Li

Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Hui Zong

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.

Roger J Packer

Gilbert Family Neurofibromatosis Institute, Children’s National Hospital, Washington, DC 20010, USA.

Yuan Zhu

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.

References

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