Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2
- Marco Giovannini1,2,4,
- Els Robanus-Maandag2,4,
- Martin van der Valk2,
- Michiko Niwa-Kawakita1,
- Vincent Abramowski1,
- Laurence Goutebroze1,
- James M. Woodruff3,
- Anton Berns2, and
- Gilles Thomas1,5
- 1INSERM U434, Fondation Jean Dausset, CEPH, 75010 Paris, France; 2Division of Molecular Genetics, Department of Animal Pathology, and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 3Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 USA
Abstract
Hemizygosity for the NF2 gene in humans causes a syndromic susceptibility to schwannoma development. However, Nf2hemizygous mice do not develop schwannomas but mainly osteosarcomas. In the tumors of both species, the second Nf2 allele is inactivated. We report that conditional homozygous Nf2 knockout mice with Cre-mediated excision of Nf2 exon 2 in Schwann cells showed characteristics of neurofibromatosis type 2. These included schwannomas, Schwann cell hyperplasia, cataract, and osseous metaplasia. Thus, the tumor suppressor function of Nf2, here revealed in murine Schwann cells, was concealed in hemizygousNf2 mice because of insufficient rate of second allele inactivation in this cell compartment. The finding of this conserved function documents the relevance of the present approach to model the human disease.
