Light Drives Optic Glioma Formation in a Cancer-Predisposition Syndrome

The cancer-predisposition syndrome neurofibromatosis 1 (NF1), caused by mutations in the NF1 tumor suppressor gene, causes tumor development in proximity to nerves. By early childhood, many patients with NF1 develop optic pathway gliomas (OPG), and it has been suggested that light exposure–induced optic nerve activity may underlie their development. To investigate this, Pan and colleagues employed a genetically engineered mouse model of Nf1 deficiency, which recapitulates the low-grade OPGs associated with NF1 in patients faithfully and with high penetrance. In this model, stimulation of retinal ganglion cells (which convey information about light conditions from the retina to the brain via the optic nerve) with blue light from six to 12 weeks of age resulted in greater optic nerve volumes. Two further insights were gained via experiments in which mice were temporarily reared in complete darkness, which diminishes retinal ganglion activity and thus visual experience, an effect that lingers for several days even after normal light exposure is restored. First, light stimulation was required for OPG development in Nf1-deficient mice: Only one of seven mice reared in complete darkness from nine weeks of age (when OPGs have generally just begun to form in this model) until 16 weeks of age developed tumors, whereas 11 out of 11 mice raised in traditional lighting (cycles of 12 hours of light and 12 hours of dark) developed tumors. Second, light stimulation was required for early-stage tumor maintenance: Just two of nine mice reared in the dark from the age of 12 weeks (when tumors have already taken hold) to 16 weeks developed OPGs. Mechanistically, retinal neuron–specific Nf1 depletion resulted in abnormally high shedding of the synaptic adhesion protein neuroligin 3 (NLGN3)—which had previously been demonstrated in xenograft models to be necessary for glioma progression—in the optic nerve upon stimulation, promoting tumorigenesis. Collectively, these findings reveal a role for light exposure in the development of OPGs in NF1 during a critical developmental time period.

Pan Y, Hysinger JD, Barron T, Schindler NF, Cobb O, Guo X, et al. NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 2021 May 26 [Epub ahead of print].

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