Neurofibromatosis type 1 (NF1), the most common
genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell
tumors in skin and large peripheral nerves. These
neoplasms, which are termed dermal and
plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal,
neurofibromas often undergo malignant progression to form
malignant peripheral nerve sheath tumors (MPNSTs), the most common
malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these
tumors. These models have been designed to address key questions including: (1) whether NF1 loss in the Schwann cell lineage is essential for
tumorigenesis; (2) what cell type(s) in the Schwann cell lineage gives rise to dermal
neurofibromas, plexiform neurofibromas and MPNSTs; (3) how the tumor microenvironment contributes to
neoplasia; (4) what additional mutations contribute to
neurofibroma-
MPNST progression; (5) what role different
neurofibromin-regulated
Ras proteins play in this process and (6) how dysregulated
growth factor signaling facilitates PNS
tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of
tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.