The Loss of Nf1 Transiently Promotes Self-Renewal but Not Tumorigenesis by Neural Crest Stem Cells

Summary Neurofibromatosis is caused by the loss of neurofibromin ( Nf1 ), leading to peripheral nervous system (PNS) tumors, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). A long-standing question has been whether these tumors arise from neural crest stem cells (NCSCs) or differentiated glia. Germline or conditional Nf1 deficiency caused a transient increase in NCSC frequency and self-renewal in most regions of the fetal PNS. However, Nf1 -deficient NCSCs did not persist postnatally in regions of the PNS that developed tumors and could not form tumors upon transplantation into adult nerves. Adult P0a-Cre + Nf1 fl/− mice developed neurofibromas, and Nf1 +/− Ink4a/Arf −/− and Nf1/p53 +/− mice developed MPNSTs, but NCSCs did not persist postnatally in affected locations in these mice. Tumors appeared to arise from differentiated glia, not NCSCs.