title: A murine model of neurofibromatosis type 2 that accurately phenocopies human schwannoma formation.
abstract: Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder resulting from germline mutations in the NF2 gene. Bilateral vestibular schwannomas, tumors on cranial nerve VIII, are pathognomonic for NF2 disease. Furthermore, schwannomas also commonly develop in other cranial nerves, dorsal root ganglia and peripheral nerves. These tumors are a major cause of morbidity and mortality, and medical therapies to treat them are limited. Animal models that accurately recapitulate the full anatomical spectrum of human NF2-related schwannomas, including the characteristic functional deficits in hearing and balance associated with cranial nerve VIII tumors, would allow systematic evaluation of experimental therapeutics prior to clinical use. Here, we present a genetically engineered NF2 mouse model generated through excision of the Nf2 gene driven by Cre expression under control of a tissue-restricted 3.9kbPeriostin promoter element. By 10 months of age, 100% of Postn-Cre; Nf2(flox/flox) mice develop spinal, peripheral and cranial nerve tumors histologically identical to human schwannomas. In addition, the development of cranial nerve VIII tumors correlates with functional impairments in hearing and balance, as measured by auditory brainstem response and vestibular testing. Overall, the Postn-Cre; Nf2(flox/flox) tumor model provides a novel tool for future mechanistic and therapeutic studies of NF2-associated schwannomas.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gehlhausen
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Biomedical Engineering and Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, IN, USA and.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Hickox
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Matthew
authors.initials: M
authors.lastname: Shew
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry.
authors.forename: Karl
authors.initials: K
authors.lastname: Staser
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Anatomy and Cell Biology.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Keshav
authors.initials: K
authors.lastname: Menon
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry.
authors.forename: Jacquelyn D
authors.initials: JD
authors.lastname: Lajiness
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Microbiology and Immunology.
authors.forename: Muithi
authors.initials: M
authors.lastname: Mwanthi
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research.
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Radiology and.
authors.forename: Paul
authors.initials: P
authors.lastname: Territo
authors.affiliation: Department of Radiology and.
authors.forename: Gary
authors.initials: G
authors.lastname: Hutchins
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nalepa
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Anatomy and Cell Biology.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry Department of Anatomy and Cell Biology.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.affiliation: Department of Biomedical Engineering and Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, IN, USA and.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heinz
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.affiliation: Department of Otolaryngology, Indiana University School of Medicine, Indianapolis, IN, USA cwyates@iupui.edu dclapp@iupui.edu.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Yates
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research Department of Biochemistry Department of Microbiology and Immunology cwyates@iupui.edu dclapp@iupui.edu.
authors.forename: D
authors.initials: D
authors.lastname: Wade Clapp
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D004195:Disease Models, Animal; D005091:Exons; D005727:Ganglia, Spinal / Q000473:pathology*; D006309:Hearing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016518:Neurofibromatosis 2 / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D025581:Neurofibromin 2 / Q000235:genetics*; D009464:Neuroma, Acoustic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000159:Vestibulocochlear Nerve / Q000473:pathology*
chemical_list: D015815:Cell Adhesion Molecules; D025581:Neurofibromin 2; C082838:Postn protein, mouse
references.citation: Science. 1987 Apr 17;236(4799):317-9
references.pmid: 3105060
references.citation: Cancer Cell. 2012 Jul 10;22(1):131-8
references.pmid: 22789544
references.citation: J Physiol. 2004 Sep 1;559(Pt 2):625-38
references.pmid: 15243133
references.citation: Cancer Res. 2004 May 15;64(10):3718-24
references.pmid: 15150133
references.citation: J Acoust Soc Am. 1998 Jul;104(1):370-7
references.pmid: 9670530
references.citation: Genes Dev. 2000 Jul 1;14(13):1617-30
references.pmid: 10887156
references.citation: N Engl J Med. 2009 Jul 23;361(4):358-67
references.pmid: 19587327
references.citation: Otol Neurotol. 2009 Sep;30(6):835-41
references.pmid: 19704365
references.citation: Dev Biol. 2007 Jul 15;307(2):340-55
references.pmid: 17540359
references.citation: Mol Cell. 2000 Jan;5(1):189-95
references.pmid: 10678181
references.citation: Hum Mol Genet. 2009 Jul 1;18(13):2378-87
references.pmid: 19357198
references.citation: Hum Mol Genet. 2001 Mar 1;10(5):507-12
references.pmid: 11181574
references.citation: PLoS One. 2012;7(9):e46132
references.pmid: 23049959
references.citation: Nat Protoc. 2010 Jan;5(1):177-90
references.pmid: 20057387
references.citation: J Assoc Res Otolaryngol. 2009 Dec;10(4):545-56
references.pmid: 19636622
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):741-54
references.pmid: 16915232
references.citation: Brain. 2002 May;125(Pt 5):996-1004
references.pmid: 11960890
references.citation: Cancer Cell. 2008 Feb;13(2):105-16
references.pmid: 18242511
references.citation: Lancet. 2009 Jun 6;373(9679):1974-86
references.pmid: 19476995
references.citation: Nat Rev Neurosci. 2005 Sep;6(9):671-82
references.pmid: 16136171
references.citation: Cell. 2013 Feb 28;152(5):1077-90
references.pmid: 23434321
references.citation: Laryngoscope. 2007 Apr;117(4):680-3
references.pmid: 17429875
references.citation: J Neurosurg. 2009 Oct;111(4):855-62
references.pmid: 19301957
references.citation: Acta Otolaryngol. 1995 May;115(3):375-81
references.pmid: 7653257
references.citation: Cell. 2008 Oct 31;135(3):437-48
references.pmid: 18984156
references.citation: Genes Dev. 1999 Apr 15;13(8):978-86
references.pmid: 10215625
references.citation: Hear Res. 1996 Apr;93(1-2):52-71
references.pmid: 8735068
references.citation: J Neuropathol Exp Neurol. 1998 Dec;57(12):1164-7
references.pmid: 9862639
references.citation: J Am Aud Soc. 1979 Mar-Apr;4(5):173-8
references.pmid: 511644
references.citation: Hear Res. 1999 Apr;130(1-2):94-107
references.pmid: 10320101