2. Academic Validation
  3. NF1 mutation drives neuronal activity-dependent initiation of optic glioma

NF1 mutation drives neuronal activity-dependent initiation of optic glioma

  • Nature. 2021 Jun;594(7862):277-282. doi: 10.1038/s41586-021-03580-6.
Yuan Pan 1,  Jared D Hysinger 1,  Tara Barron 1,  Nicki F Schindler 1,  Olivia Cobb 2,  Xiaofan Guo 2,  Belgin Yalçın 1,  Corina Anastasaki 2,  Sara B Mulinyawe 1,  Anitha Ponnuswami 1,  Suzanne Scheaffer 2,  Yu Ma 2,  Kun-Che Chang 3,  Xin Xia 3,  Joseph A Toonen 2,  James J Lennon 1,  Erin M Gibson 1 4,  John R Huguenard 1,  Linda M Liau 5,  Jeffrey L Goldberg 3,  Michelle Monje  # 6 7 8 9 10,  David H Gutmann  # 11
Affiliations

Affiliations

  • 1 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • 2 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
  • 3 Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA, USA.
  • 4 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • 5 Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, USA.
  • 6 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
  • 7 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
  • 8 Department of Pediatrics, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
  • 9 Department of Neurosurgery, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
  • 10 Department of Pathology, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
  • 11 Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. gutmannd@wustl.edu.
  • # Contributed equally.
PMID: 34040258 DOI: 10.1038/s41586-021-03580-6
Abstract

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of Cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) Cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 Cancer predisposition syndrome.

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