Perinatal or Adult Nf1 Inactivation Using Tamoxifen-Inducible PlpCre Each Cause Neurofibroma Formation

Abstract

Plexiform neurofibromas are peripheral nerve sheath tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. To understand whether neurofibroma formation is possible after birth, we induced Nf1 loss of function with an inducible proteolipid protein Cre allele. Perinatal loss of Nf1 resulted in the development of small plexiform neurofibromas late in life, while loss in adulthood caused large plexiform neurofibromas and morbidity beginning 4 months after onset of Nf1 loss. A conditional EGFP reporter allele identified cells showing recombination, including peripheral ganglia satellite cells, peripheral nerve S100β+ myelinating Schwann cells, and peripheral nerve p75+ cells. Neurofibromas contained cells with Remak bundle disruption but no recombination within GFAP+ non-myelinating Schwann cells. Extramedullary lympho-hematopoietic expansion was also observed in PlpCre;Nf1fl/fl mice. These tumors contained EGFP+/Sca-1+ stromal cells among EGFP-negative lympho-hematopoietic cells indicating a non-cell autonomous effect and unveiling a role of Nf1-deleted microenvironment on lympho-hematopoietic proliferation in vivo. Together these findings define a tumor suppressor role for Nf1 in the adult and narrow the range of potential neurofibroma-initiating cell populations.

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

“…NF1 is a kind of tumor suppressor gene encoding neurofibromin, the dysfunction of which leads to multiple neurofibromas through Ras activation (4,5). Ras activation, in turn, triggers the activation of 2 downstream pathways: the mitogen-activated protein kinase (MAPK) pathway and the AKT/mTOR pathway.…”

The role of the immune system in neurofibromatosis type 1-associated nervous system tumors

“…However, the dependence on Nf1 heterozygous stroma may vary with the developmental stage at which the neuro fibromas initiate, since tumors initiating through Nf1 loss in Krox20 + cells require Nf1 heterozygous bone marrow, whereas Nf1 loss in Dhh + cells or in postnatal Plp + cells drives neuro fibromas on a wildtype stroma background [67,94]. Alternatively, differences in genetic background or pathogen status of the mice in these different experiments could explain the variation in the requirement for Nf1 heterozygous stroma.…”

Eliminating barriers to personalized medicine

“…With the development of numerous accurate small-animal (genetically engineered mouse; GEM) models of NF1-associated nervous system tumors (table 1), [8][9][10][11][12][13][14][15][16][17][18] the creation of the NF Clinical Trials Consortium, 19 and the establishment of response criteria for NF1 clinical trials, 20 the stage has been set for the discovery and validation of promising therapeutic strategies and their translation to people affected with NF1. However, despite these advances, there are currently no effective therapies, which likely reflects the striking biological and clinical heterogeneity inherent to this condition.…”