Neurofibromatosis 1 (NF1) is an inherited tumor-predisposition syndrome in which mutations in the neurofibromin gene NF1 cause various dysfunctions in the nervous system, including pain that substantially diminishes quality of life. Pain can be both tumor-dependent and tumor-independent and is challenging to manage therapeutically. Mice with homozygous loss of Nf1 in Schwann cells exhibit pain before tumors form, and this pain is associated with increased gene expression of glial cell line–derived neurotrophic factor (GDNF). Here, we investigated the cause of increased GDNF production and its downstream target cells in a mouse model of NF1. We found that Schwann cells were the dominant source of GDNF in NF1 mice. Schwann cell–derived GDNF activated the receptor GFRα1 on high-threshold mechanoreceptors and polymodal C-fibers, which mediated mechanical hypersensitivity in mice. Treating the mice with pharmacological inhibitors of mitogen-activated protein kinase (MAPK) signaling reduced pain-like behaviors and the expression of GDNF at the mRNA and protein levels in Schwann cells. The findings provide insight into the signaling pathways that underlie tumor-independent pain in NF1 and identify a targetable pathway for therapeutic intervention.
Raut et al. (Tue,) studied this question.