Abstract 355: Generation of a murine model of Neurofibromatosis Type 2 that accurately recapitulates the spontaneous development of vestibular and spinal schwannomas found in NF2 patients.
Authors: Gehlhausen Jeff R. , Park Su Jung , Shew Matthew , Clapp Wade , Yates Charles 
Published: August 2014

Abstract
Neurofibromatosis type 2 (NF2) is a genetic disease resulting from germline loss of the NF2 tumor suppressor gene. The hallmark of NF2 is hearing and vestibular loss of function in young adults caused by the development of vestibular schwannomas, which occur bilaterally in nearly all patients and are associated with homozygous loss of NF2. Individuals affected with NF2 also acquire schwannomas of other cranial, spinal and peripheral nerves. Importantly, non-familial schwannomas, the most common tumor of the peripheral nervous system, are also caused by bi-allelic loss of NF2 gene function. A major limitation in the identification of genetic and pharmacologic targets for schwannomas has been the lack of a robust preclinical model that accurately recapitulates human NF2 disease. In order to develop a more robust model, we intercrossed a mouse expressing Cre Recombinase under the control of the 3.9PeriCre promoter with an Nf2 conditional knockout mouse previously generated by Dr. Marco Giovannini to conditionally ablate Nf2 in neural crest-derived cell populations. Histological analysis of the dorsal root ganglion (DRG) and proximal spinal nerves of 3.9PeriCre+;Nf2flox/flox mice revealed that intercrossed mice spontaneously develop tumors between 8 and 10 months at every single spinal level. Microscopic analysis implicated these tumors as schwannomas, as they display a dense pattern of cellularity consistent with the established criteria of GEM schwannoma, including S100β1 positivity. Quantitation of the DRG volume indicated that 3.9PeriCre+ mice have a statistically significant increase when compared to 3.9PeriCre- littermates. FDG-PET studies corroborated this finding, as comparative studies showed an increase in the metabolic activity of paraspinal tumors found in 3.9PeriCre+ mice. Auditory Brainstem Response testing has revealed that 3.9PeriCre+ mice acquire an age-dependent increase in hearing threshold by 8 months when compared to age-matched 3.9PeriCre- controls. Histological analysis of Cranial Nerve VIII confirmed that the hearing loss was directly associated with the development of vestibular schwannomas. To test for concomitant vestibular loss of function, three different behavioral studies (contact righting, trunk curl, and swim) were performed to isolate and test the integrity of the vestibular sense in 3.9PeriCre;Nf2flox/flox mice. These studies indicated that 3.9PeriCre+ mice develop vestibular deficits, as all three studies identified highly significant differences between the two genotypes. Collectively, these genetically engineered mice acquire a physiologic phenotype that closely recapitulates important features of human NF2 disease and provides opportunities for testing putative therapeutic targets using genetic intercrosses or novel small molecule inhibitors.
Citation Format: Jeff R. Gehlhausen, Su Jung Park, Matthew Shew, Wade Clapp, Charles Yates. Generation of a murine model of Neurofibromatosis Type 2 that accurately recapitulates the spontaneous development of vestibular and spinal schwannomas found in NF2 patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2013-355