TARGETED DISRUPTION OF THE NEUROFIBROMATOSIS TYPE-1 GENE LEADS TO DEVELOPMENTAL ABNORMALITIES IN HEART AND VARIOUS NEURAL CREST-DERIVED TISSUES

The neurofibromatosis (NF1) gene shows significant homology to mammali an GAP and is an important regulator of the ras signal transduction pa thway. To study the function of NF1 in normal development and to try a nd develop a mouse model of NF1 disease, we have used gene targeting i n ES cells to generate mice carrying a null mutation at the mouse Nf1 locus. Although heterozygous mutant mice, aged up to 10 months, have n ot exhibited any obvious abnormalities, homozygous mutant embryos die in utero. Embryonic death is likely attributable to a severe malformat ion of the heart. Interestingly, mutant embryos also display hyperplas ia of neural crest-derived sympathetic ganglia. These results identify new roles for NF1 in development and indicate that some of the abnorm al growth phenomena observed in NE1 patients can be recapitulated in n eurofibromin-deficient mice.