Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

• Cell lineage tracing reveals an embryonic nerve root origin of plexiform neurofibroma
• Embryonic PLP+GAP43+ precursors are the cells of origin for plexiform neurofibroma
• A model of plexiform neurofibroma for preclinical therapeutic screening is generated
• Inhibition of Ras/Raf/MEK/ERK signaling pathways can prevent neurofibroma progression

SummaryNeurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43+ PLP+ precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline neurofibroma model for preclinical drug screening to identify effective therapies. The identity of the tumor cell of origin and facility for isolation and expansion provides fertile ground for continued analysis to define factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients.

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