DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Nf1 Mutation Drives Neuronal-Activity-Dependent Initiation of Optic Glioma

Posted November 17, 2021

Dr. Michelle Monje-Deisseroth, Stanford University
Dr. Yuan Pan, Stanford University

Neurons are essential components of the tumor microenvironment, and their activity has been shown to influence the growth of tumors. Although the role of neurons in tumor progression has previously been demonstrated, their role in tumor initiation is less clear. An estimated 15% of individuals with neurofibromatosis 1 (NF1) cancer predisposition syndrome develop low-grade optic pathway gliomas (OPGs) during early childhood, raising the possibility that postnatal light-induced neuronal activity of the optic nerve drives tumor initiation. Childhood NF1-OPGs have a predictable anatomical and temporal incidence and occur in a neural circuit that can be experimentally manipulated.

Dr. Michelle Monje-Deisseroth, Stanford University Dr. Michelle Monje-Deisseroth, Stanford University
Dr. Yuan Pan, Stanford University Dr. Yuan Pan,
Stanford University

As a Fiscal Year 2015 (FY15) New Investigator Award (NIA) recipient, Dr. Monje-Deisseroth, in collaboration with Dr. David Gutmann and FY18 Early Career Investigator Award recipient, Dr. Yuan Pan, have been studying the influence of neuronal activity on the pathogenesis of NF1-OPGs. Their studies aim to determine whether light-induced neuronal activity of the optic nerve is required for the initiation and maintenance of NF1-OPGs. Drs. Monje-Deisseroth and Pan used a genetically engineered mouse model with specific Nf1 genetic mutations that result in NF1-OPGs that grow around the axons of retinal ganglion cells (RGCs). RGCs are neurons that transmit light-related information from the retina to the brain via the optic nerve. To inhibit light-induced optic nerve neuronal activity, the Nf1-mutant mice were reared in complete darkness from 6 weeks of age (when optic gliomas had not yet formed) until 12 weeks of age, when the mice were shifted over to a 12-hour cycle of light and dark exposure for an additional 12 weeks. Unlike the Nf1-mutant mice raised in a regular light/dark cycle that all developed NF1-OPGs, Nf1-mutant mice reared in darkness did not show signs of tumor formation, even when they were re-exposed to light following the dark-rearing. The results indicate that there is a window of intervention for NF1-OPG initiation. Specifically, this study demonstrated that initiation of NF1-OPGs depends on visual experience during a critical period in which Nf1-mutant mice are susceptible to tumorigenesis. Furthermore, findings from this study showed that the germline Nf1 mutation in stromal cells resulted in increased shedding of the protein neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity and that genetic loss of Nlgn3 or pharmacological inhibition of NLGN3 shedding blocked the formation and progression of NF1-OPGs. Dr. Monje-Deisseroth’s group has also demonstrated in past work that neuronal activity-dependent NLGN3 signaling drives high-grade glioma progression, indicating the critical role of NLGN3 in glioma pathophysiology and highlighting a potential target for therapeutic intervention.

Collectively, these studies establish a role for neuronal activity in the development of some types of brain tumor and emphasize the role of Nf1-mutation-mediated dysregulation of neuronal signaling pathways, revealing new avenues of discovery for a therapeutic strategy to reduce OPG incidence or mitigate tumor progression.


Links:

Public and Technical Abstracts: The Role of Neuronal Activity in NF1-Associated Optic Pathway Gliomagenesis

Public and Technical Abstracts: Defining the Role of Neuronal Activity on the Initiation and Growth of Neurofibromatosis Type 1 (NF1)-Associated Optic Glioma

Pan, Y., Hysinger, J.D., Barron, T. et al. Nf1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 594, 277–282 (2021).

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Last updated Wednesday, November 17, 2021