Neuronal activity is emerging as a driver of central and peripheral nervous system
cancers. Here, we examined neuronal physiology in mouse models of the
tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system
cancers. We show that central and peripheral nervous system neurons from mice with
tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent
tumor-promoting paracrine factors. We discovered a
neurofibroma mitogen (
COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that
neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking
neurofibromas or
optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated
tumors. The hyperexcitability of
tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated
cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and
tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify
tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.