Modelling Neurofibroma Formation in the Culture Dish.

Abstract

Abstract : We developed methods to purify Schwann cells from mouse embryos mutant at NF1 and compared mutant cells to wild type Schwann cells. NF1-deficient cells showed abnormalities in proliferation, differentiation, ability to stimulate angiogenic reactions and invade basement membranes. A gene dosage effect was confirmed; Schwann cells heterozygous at NF1 were intermediate in phenotype to wild type or null cells. Activation of Ras in Schwann cells correlated with loss of NF1, phenotypes of Schwann cells deficient in NF1 were mimicked in Schwann cells expressing activated Ras, and drugs that inhibit Ras function reversed some phenotypes of NF1-deficient cells. Together, the data demonstrate that a major NF1 function in Schwann cells is regulation of Ras activation. We propose that protein farnesyl transferase innibitors might be useful to correct phenotypes of benign, NF1-deficient, Schwann cells in human patients. Additional studies defined the first cellular abnormality in fibroblasts lacking NF1, a failure to form perineurium; fibroblast abnormalities occurred mainly or solely in null cells. Experiments aimed at testing if NF1-deficient fibroblasts have calcium handling abnormalities were inconclusive. The data demonstrate that both Schwann cells and fibroblasts manifest cell autonomous abnormalities as a consequence of NF1 mutations.