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What Have We Learned from Murine Models of Otitis Media?

  • OTITIS (DP SKONER, SECTION EDITOR)
  • Published:
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Abstract

Otitis media (OM) is a common cause of childhood hearing loss. The large medical costs involved in treating this condition have meant that research to understand the pathology of this disease and identify new therapeutic interventions is important. There is evidence that susceptibility to OM has a significant genetic component, although little is known about the key genetic pathways involved. Mouse models for disease have become an important resource to understand a variety of human pathologies, including OM, due to the ability to easily manipulate their genetic components. This has enabled researchers to create models of acute OM, and has aided in the identification of a number of new genes associated with chronic disease, through the use of mutagenesis programs. The use of mouse models has identified a number of key molecular signalling pathways involved in the development of this condition, with genes identified from models shown to be associated with human OM.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Monasta L, Ronfani L, Marchetti F, et al. Burden of disease caused by otitis media: systematic review and global estimates. PLoS ONE. 2012;7.

  2. Davidson J, Hyde M, Alberti P. Epidemiologic patterns in childhood hearing loss: a review. Int J Pediatr Otorhinolaryngol. 1989;17:239–66.

    PubMed  CAS  Google Scholar 

  3. Browning G, Rovers M, Williamson I, et al. Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. Cochrane Database Syst Rev. 2010;10.

  4. Trune D, Zheng Q. Mouse models for human otitis media. Brain Res. 2009;1277:90–103.

    PubMed  CAS  Google Scholar 

  5. Sood S, Waddell A. Accurate consent for insertion and later removal of grommets. The Journal of laryngology and otology. 2007;121:338–40.

    PubMed  CAS  Google Scholar 

  6. Daly K, Hoffman H, Kvaerner K, et al. Epidemiology, natural history, and risk factors: panel report from the Ninth International Research Conference on Otitis Media. Int J Pediatr Otorhinolaryngol. 2010;74:231–40.

    PubMed  Google Scholar 

  7. Rosenthal N, Brown S. The mouse ascending: perspectives for human-disease models. Nat Cell Biol. 2007;9:993–9.

    PubMed  CAS  Google Scholar 

  8. Zheng Q, Hardisty-Hughes R, Brown S. Mouse models as a tool to unravel the genetic basis for human otitis media. Brain Res. 2006;1091:9–15.

    PubMed  CAS  Google Scholar 

  9. Ryan A, Ebmeyer J, Furukawa M, et al. Mouse models of induced otitis media. Brain Res. 2006;1091:3–8.

    PubMed  CAS  Google Scholar 

  10. Rye M, Bhutta M, Cheeseman M, et al. Unraveling the genetics of otitis media: from mouse to human and back again. Mamm Genome. 2011;22(1–2):66–82.

    PubMed  CAS  Google Scholar 

  11. Brown S, Wurst W, Kühn R, et al. The functional annotation of mammalian genomes: the challenge of phenotyping. Annu Rev Genet. 2009;43:305–33.

    PubMed  CAS  Google Scholar 

  12. Brown S, Hancock J. The mouse genome. Genome Dynamics. 2006;2:33–45.

    PubMed  CAS  Google Scholar 

  13. Brown S, Hardisty-Hughes R, Mburu P. Quiet as a mouse: dissecting the molecular and genetic basis of hearing. Nat Rev Genet. 2008;9:277–90.

    PubMed  CAS  Google Scholar 

  14. Bhutta M. Mouse models of otitis media: strengths and limitations. Otolaryngol Head Neck Surg. 2012;147:611–4.

    PubMed  Google Scholar 

  15. Stol K, van Selm S, van den Berg S, et al. Development of a non-invasive murine infection model for acute otitis media. Microbiology. 2009;155:4135–44.

    PubMed  CAS  Google Scholar 

  16. Sabirov A, Metzger D. Mouse models for the study of mucosal vaccination against otitis media. Vaccine. 2008;26:1501–24.

    PubMed  CAS  Google Scholar 

  17. Austin C, Battey J, Bradley A, et al. The knockout mouse project. Nat Genet. 2004;36:921–4.

    PubMed  CAS  Google Scholar 

  18. Nolan P, Peters J, Strivens M, et al. A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat Genet. 2000;25:440–3.

    PubMed  CAS  Google Scholar 

  19. Acevedo-Arozena A, Wells S, Potter P, et al. ENU mutagenesis, a way forward to understand gene function. Annual review of genomics and human genetics. 2008;9:49–69.

    PubMed  CAS  Google Scholar 

  20. Giebink G. Immunoprophylaxis of otitis media. Adv Exp Med Biol. 1991;303:149–58.

    PubMed  CAS  Google Scholar 

  21. Akira S, Takeda. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.

    PubMed  CAS  Google Scholar 

  22. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology. 2010;11:373–84.

    PubMed  CAS  Google Scholar 

  23. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.

    PubMed  CAS  Google Scholar 

  24. Leichtle A, Hernandez M, Lee J, et al. The role of DNA sensing and innate immune receptor TLR9 in otitis media. Innate Immunity. 2012;18:3–13.

    PubMed  CAS  Google Scholar 

  25. Hirano T, Kodama S, Fujita K, et al. Role of Toll-like receptor 4 in innate immune responses in a mouse model of acute otitis media. FEMS Immunology and Medical Microbiology. 2007;49:75–83.

    PubMed  CAS  Google Scholar 

  26. Leichtle A, Hernandez M, Pak K, et al. TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media. Innate immunity. 2009;15:205–15.

    PubMed  CAS  Google Scholar 

  27. Hernandez M, Leichtle A, Pak K, et al. Myeloid differentiation primary response gene 88 is required for the resolution of otitis media. J Infect Dis. 2008;198:1862–9.

    PubMed  Google Scholar 

  28. Fritz J, Girardin S. How Toll-like receptors and Nod-like receptors contribute to innate immunity in mammals. Journal of Endotoxin Research. 2005;11:390–4.

    PubMed  CAS  Google Scholar 

  29. He Y, Scholes M, Wiet G, et al. Complement activation in pediatric patients with recurrent acute otitis media. Int J Pediatr Otorhinolaryngol. 2013. Ahead of print.

  30. Tong H, Li Y, Stahl G, et al. Enhanced susceptibility to acute pneumococcal otitis media in mice deficient in complement C1qa, factor B, and factor B/C2. Infect Immun. 2010;78:976–83.

    PubMed  CAS  Google Scholar 

  31. Bogaert D, Thompson C, Trzcinski K, et al. The role of complement in innate and adaptive immunity to pneumococcal colonization and sepsis in a murine model. Vaccine. 2010;28:681–5.

    PubMed  CAS  Google Scholar 

  32. Moraes F, Nóvoa A, Jerome-Majewska LA, et al. Tbx1 is required for proper neural crest migration and to stabilize spatial patterns during middle and inner ear development. Mech Dev. 2005;122:199–212.

    PubMed  CAS  Google Scholar 

  33. Han F, Yu H, Zhang J, et al. Otitis media in a mouse model for Down syndrome. Int J Exp Pathol. 2009;90:480–8.

    PubMed  Google Scholar 

  34. Sullivan K, Jawad A, Randall P, et al. Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin Immunol Immunopathol. 1998;86:141–6.

    PubMed  CAS  Google Scholar 

  35. Aggarwal V, Morrow B. Genetic modifiers of the physical malformations in velo-cardio-facial syndrome/DiGeorge syndrome. Developmental Disabilities Research Reviews. 2008;14:19–25.

    PubMed  Google Scholar 

  36. Hoffman J, Ciprero K, Sullivan K, et al. Immune abnormalities are a frequent manifestation of Kabuki syndrome. Am J Med Genet. 2005;135:278–81.

    PubMed  Google Scholar 

  37. Jyonouchi S, McDonald-McGinn D, Bale S, et al. CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome: a comparison of immunologic and nonimmunologic phenotypic features. Pediatrics. 2009;123:7.

    Google Scholar 

  38. Kusters MA, Verstegen R, Gemen E, et al. Intrinsic defect of the immune system in children with Down syndrome: a review. Clinical and Experimental Immunology. 2009;156:189–93.

    PubMed  CAS  Google Scholar 

  39. Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clinical and Experimental Immunology. 2011;164:9–16.

    PubMed  CAS  Google Scholar 

  40. Bhutta M. Chronic otitis media in mucopolysaccharidosis may not be due to Eustachian tube dysfunction. Int J Pediatr Otorhinolaryngol. 2011;75:140–1.

    PubMed  Google Scholar 

  41. Schachern P, Cureoglu S, Tsuprun V, et al. Age-related functional and histopathological changes of the ear in the MPS I mouse. Int J Pediatr Otorhinolaryngol. 2007;71:197–203.

    PubMed  Google Scholar 

  42. Jung S-C, Park E-S, Choi E, et al. Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene therapy. Mol Cells. 2010;30:13–8.

    PubMed  CAS  Google Scholar 

  43. Heldermon C, Hennig A, Ohlemiller K, et al. Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B. PLoS One. 2007;2(8).

  44. Vogler C, Levy B, Galvin N, et al. A novel model of murine mucopolysaccharidosis type VII due to an intracisternal a particle element transposition into the beta-glucuronidase gene: clinical and pathologic findings. Pediatr Res. 2001;49:342–8.

    PubMed  CAS  Google Scholar 

  45. • Hong S, Chu H, Kim K, et al. Auditory characteristics and therapeutic effects of enzyme replacement in mouse model of the mucopolysaccharidosis (MPS) II. Am J Med Genet. 2012;158A:2131–8. The research outlined in this paper establishes an important link to therapeutics for syndromic OM.

    PubMed  Google Scholar 

  46. Voronina V, Takemaru K-I, Treuting P, et al. Inactivation of Chibby affects function of motile airway cilia. J Cell Biol. 2009;185:225–33.

    PubMed  CAS  Google Scholar 

  47. Ibañez-Tallon I, Gorokhova S, Heintz N. Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Hum Mol Genet. 2002;11:715–21.

    PubMed  Google Scholar 

  48. Lucas J, Adam E, Goggin P, et al. Static respiratory cilia associated with mutations in Dnahc11/DNAH11: a mouse model of PCD. Hum Mutat. 2012;33:495–503.

    PubMed  CAS  Google Scholar 

  49. Agius A, Wake M, Pahor A, et al. Nasal and middle ear ciliary beat frequency in chronic suppurative otitis media. Clinical Otolaryngology and Allied Sciences. 1995;20:470–4.

    PubMed  CAS  Google Scholar 

  50. Gurr A, Stark T, Pearson M, et al. The ciliary beat frequency of middle ear mucosa in children with chronic secretory otitis media. Eur Arch Otorhinolaryngol. 2009;266:1865–70.

    PubMed  Google Scholar 

  51. Takeuchi K, Saida S, Majima Y, et al. The effect of middle ear effusions from children on in vitro ciliary activity. Eur Arch Otorhinolaryngol. 1990;247:323–5.

    PubMed  CAS  Google Scholar 

  52. Ohashi Y, Nakai Y, Ohno Y, et al. Effects of human middle ear effusions on the mucociliary system of the tubotympanum in the guinea pig. Eur Arch Otorhinolaryngol. 1995;252:35–41.

    PubMed  CAS  Google Scholar 

  53. Mason P, Adam E, Prior M, et al. Effect of bacterial endotoxin and middle ear effusion on ciliary activity: implications for otitis media. The Laryngoscope. 2002;112:676–80.

    PubMed  Google Scholar 

  54. Wake M, Smallman L. Ciliary beat frequency of nasal and middle ear mucosa in children with otitis media with effusion. Clinical Otolaryngology and Allied Sciences. 1992;17:155–7.

    PubMed  CAS  Google Scholar 

  55. Xu P, Adams J, Peters H, et al. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet. 1999;23:113–7.

    PubMed  CAS  Google Scholar 

  56. Depreux F, Darrow K, Conner D, et al. Eya4-deficient mice are a model for heritable otitis media. J Clin Invest. 2008;118:651–8.

    PubMed  CAS  Google Scholar 

  57. Okabe Y, Sano T, Nagata S. Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature. 2009;460:520–4.

    PubMed  CAS  Google Scholar 

  58. Zhang Y, Knosp B, Maconochie M, et al. A comparative study of Eya1 and Eya4 protein function and its implication in branchio-oto-renal syndrome and DFNA10. JARO. 2004;5:295–304.

    PubMed  Google Scholar 

  59. Wayne S, Robertson N, DeClau F, et al. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet. 2001;10:195–200.

    PubMed  CAS  Google Scholar 

  60. Hildebrand M, Coman D, Yang T, et al. A novel splice site mutation in EYA4 causes DFNA10 hearing loss. Am J Med Genet. 2007;143A:1599–604.

    PubMed  CAS  Google Scholar 

  61. Pfister M, Tóth T, Thiele H, et al. A 4-bp insertion in the eya-homologous region (eyaHR) of EYA4 causes hearing impairment in a Hungarian family linked to DFNA10. Mol Med. 2002;8:607–11.

    PubMed  CAS  Google Scholar 

  62. Baldwin A. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–83.

    PubMed  CAS  Google Scholar 

  63. Parkinson N, Hardisty-Hughes R, Tateossian H, et al. Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media. PLoS Genetics. 2006;2(10).

  64. Schmidt-Ullrich R, Aebischer T, Hülsken J, et al. Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development. 2001;128:3843–53.

    PubMed  CAS  Google Scholar 

  65. Alliston T, Ko T, Cao Y, et al. Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1. J Biol Chem. 2005;280:24227–37.

    PubMed  CAS  Google Scholar 

  66. Izutsu K, Kurokawa M, Imai Y, et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood. 2001;97:2815–22.

    PubMed  CAS  Google Scholar 

  67. Kurokawa M, Mitani K, Yamagata T, et al. The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. EMBO J. 2000;19:2958–68.

    PubMed  CAS  Google Scholar 

  68. • Xu X, Woo C-H, Steere R, et al. EVI1 acts as an inducible negative-feedback regulator of NF-κB by inhibiting p65 acetylation. J Immunol. 2012;188:6371–80. The authors have shown a novel role for Evi1 in regulating NFkB. A mutation within Evi1 is the cause of the OM phenotype observed in Junbo, and this research provides additional information regarding the role this mutation plays in this chronic OM mouse model.

    PubMed  CAS  Google Scholar 

  69. Hardisty R, Erven A, Logan K, et al. The deaf mouse mutant Jeff (Jf) is a single gene model of otitis media. JARO. 2003;4:130–8.

    PubMed  Google Scholar 

  70. • Tateossian H, Morse S, Parker A, et al. Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease. Hum Mol Genet. 2013. Ahead of print. This paper further supports the role of TGFβ signalling in OM pathogenesis.

  71. Yoshimura A, Wakabayashi Y, Mori T, et al. Cellular and molecular basis for the regulation of inflammation by TGF-beta. J Biochem. 2010;147:781–92.

    PubMed  CAS  Google Scholar 

  72. Li M, Wan Y, Sanjabi S, et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.

    PubMed  CAS  Google Scholar 

  73. Heldin C, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–71.

    PubMed  CAS  Google Scholar 

  74. Hardisty-Hughes R, Tateossian H, Morse S, et al. A mutation in the F-box gene, Fbxo11, causes otitis media in the Jeff mouse. Hum Mol Genet. 2006;15:3273–9.

    PubMed  CAS  Google Scholar 

  75. Hindley C, McDowell G, Wise H, et al. Regulation of cell fate determination by Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligases. Int J Dev Biol. 2011;55:249–60.

    PubMed  CAS  Google Scholar 

  76. Abida W, Nikolaev A, Zhao W, et al. FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity. J Biol Chem. 2007;282:1797–804.

    PubMed  CAS  Google Scholar 

  77. Cordenonsi M, Dupont S, Maretto S, et al. Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell. 2003;113:301–14.

    PubMed  CAS  Google Scholar 

  78. Tateossian H, Hardisty-Hughes R, Morse S, et al. Regulation of TGF-beta signalling by Fbxo11, the gene mutated in the Jeff otitis media mouse mutant. Pathogenetics. 2009;2:5.

    PubMed  Google Scholar 

  79. Wotton D, Lo R, Lee S, et al. A Smad transcriptional corepressor. Cell. 1999;97:29–39.

    PubMed  CAS  Google Scholar 

  80. Seo S, Ferrand N, Faresse N, et al. Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-beta signaling. Molecular Cell. 2006;23:547–59.

    PubMed  CAS  Google Scholar 

  81. Emonts M, Veenhoven R, Wiertsema S, et al. Genetic polymorphisms in immunoresponse genes TNFA, IL6, IL10, and TLR4 are associated with recurrent acute otitis media. Pediatrics. 2007;120:814–23.

    PubMed  Google Scholar 

  82. Lee Y, Kim C, Shim J, et al. Toll-like receptors 2 and 4 and their mutations in patients with otitis media and middle ear effusion. Clinical and Experimental Otorhinolaryngology. 2008;1:189–95.

    PubMed  Google Scholar 

  83. Segade F, Daly K, Allred D, et al. Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study. Arch Otolaryngol Head Neck Surg. 2006;132:729–33.

    PubMed  Google Scholar 

  84. • Rye M, Wiertsema S, Scaman E, et al. FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children. Genes and Immunity. 2011;12:352–9. This paper demonstrates an association for mutations in FBXO11 in the human population for susceptibility to OM. Fbxo11 was discovered as the causative gene in the Jeff mouse model of chronic OM.

    PubMed  CAS  Google Scholar 

  85. Daly K, Brown W, Segade F, et al. Chronic and recurrent otitis media: a genome scan for susceptibility loci. Am J Hum Genet. 2004;75:988–97.

    PubMed  CAS  Google Scholar 

  86. Tabor H, Risch N, Myers R. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet. 2002;3:391–7.

    PubMed  CAS  Google Scholar 

  87. Cheeseman M, Tyrer H, Williams D, et al. HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. PLoS Genetics. 2011;7.

  88. Melhus A, Ryan A. A mouse model for acute otitis media. APMIS. 2003;111:989–94.

    PubMed  Google Scholar 

  89. Nurtdinov R, Artamonova I, Mironov A, et al. Low conservation of alternative splicing patterns in the human and mouse genomes. Hum Mol Genet. 2003;12:1313–20.

    PubMed  CAS  Google Scholar 

  90. Brown S, Hardisty R. Mutagenesis strategies for identifying novel loci associated with disease phenotypes. Seminars in Cell and Developmental Biology. 2003;14:19–24.

    PubMed  CAS  Google Scholar 

  91. Bhogal N, Combes R. The relevance of genetically altered mouse models of human disease. ATLA. 2006;34:429–54.

    PubMed  CAS  Google Scholar 

  92. MacArthur C, Hefeneider S, Kempton J, Trune D. C3H/HeJ mouse model for spontaneous chronic otitis media. The Laryngoscope. 2006;116(7):1071–9.

    PubMed  Google Scholar 

  93. Leichtle A, Hernandez M, Pak K, et al. The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery. BMC immunology. 2009;10:45.

    PubMed  Google Scholar 

  94. Rivkin A, Palacios S, Pak K, et al. The role of Fas-mediated apoptosis in otitis media: observations in the lpr/lpr mouse. Hearing Res. 2005;207(1–2):110–6.

    CAS  Google Scholar 

  95. Leichtle A, Hernandez M, Ebmeyer J, et al. CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice. J Immunol. 2010;184(6):3087–97.

    PubMed  CAS  Google Scholar 

  96. Ebmeyer J, Leichtle A, Hernandez M, et al. TNFA deletion alters apoptosis as well as caspase 3 and 4 expression during otitis media. BMC immunology. 2011;12:12.

    PubMed  CAS  Google Scholar 

  97. Lim J, Jono H, Koga T, et al. Tumor suppressor CYLD acts as a negative regulator for non-typeable Haemophilus influenza-induced inflammation in the middle ear and lung of mice. PloS ONE. 2007;2(10).

  98. Tsuchiya K, Komori M, Zheng Q, et al. Interleukin-10 is an essential modulator of mucoid metaplasia in a mouse otitis media model. Ann Otol Rhinol Laryngol. 2008;117(8):630–6.

    PubMed  Google Scholar 

  99. Vogel P, Read R, Hansen G, et al. Congenital hydrocephalus in genetically engineered mice. Vet Pathol. 2012;49(1):166–81.

    PubMed  CAS  Google Scholar 

  100. Kunimoto K, Yamazaki Y, Nishida T, et al. Coordinated ciliary beating requires Odf2-mediated polarization of basal bodies via basal feet. Cell. 2012;148(1–2):189–200.

    PubMed  CAS  Google Scholar 

  101. Vogel P, Hansen G, Fontenot G, Read R. Tubulin tyrosine ligase-like 1 deficiency results in chronic rhinosinusitis and abnormal development of spermatid flagella in mice. Vet Pathol. 2010;47(4):703–12.

    PubMed  CAS  Google Scholar 

  102. Tian C, Yu H, Yang B, et al. Otitis media in a new mouse model for CHARGE syndrome with a deletion in the Chd7 gene. PloS ONE. 2012;7(4).

  103. Maison S, Le M, Larsen E, et al. Mice lacking adrenergic signaling have normal cochlear responses and normal resistance to acoustic injury but enhanced susceptibility to middle-ear infection. JARO. 2010;11(3):449–61.

    PubMed  Google Scholar 

  104. Humbert P, Rogers C, Ganiatsas S, et al. E2F4 is essential for normal erythrocyte maturation and neonatal viability. Molecular Cell. 2000;6(2):281–91.

    PubMed  CAS  Google Scholar 

  105. Pau H, Fuchs H, de Angelis M, Steel K. Hush puppy: a new mouse mutant with pinna, ossicle, and inner ear defects. The Laryngoscope. 2005;115(1):116–24.

    PubMed  Google Scholar 

  106. Calvert J, Dedos S, Hawker K, et al. A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice. Mamm Genome. 2011;22(5–6):290–305.

    PubMed  Google Scholar 

  107. Hilton J, Lewis M, Grati Mh, et al. Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice. Genome Biol. 2011;12(9).

  108. Zhang Y, Yu H, Xu M, et al. Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies. Am J Pathol. 2012;181(3):761–74.

    PubMed  CAS  Google Scholar 

  109. Chen J, Ingham N, Clare S, et al. Mcph1-Deficient Mice Reveal a Role for MCPH1 in Otitis Media. PloS ONE. 2013;8(3).

  110. Giovannini M, Robanus-Maandag E, van der Valk M, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 2000;14(13):1617–30.

    PubMed  CAS  Google Scholar 

  111. Kerschner J, Hong W, Taylor S, et al. A novel model of spontaneous otitis media with effusion (OME) in the Oxgr1 knock-out mouse. Int J Pediatr Otorhinolaryngol. 2013;77(1):79–84.

    PubMed  Google Scholar 

  112. Yang A, Walker N, Bronson R, et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000;404(6773):99–103.

    PubMed  CAS  Google Scholar 

  113. Megerian C, Semaan M, Aftab S, et al. A mouse model with postnatal endolymphatic hydrops and hearing loss. Hearing Res. 2008;237(1–2):90–105.

    CAS  Google Scholar 

  114. Han F, Yu H, Li P, et al. Mutation in Phex gene predisposes BALB/c-Phex(Hyp-Duk)/Y mice to otitis media. PloS ONE. 2012;7(9).

  115. Eriksson P-O, Li J, Ny T, Hellström S. Spontaneous development of otitis media in plasminogen-deficient mice. IJMM. 2006;296(7):501–9.

    PubMed  Google Scholar 

  116. Noben-Trauth K, Latoche J. Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse. J Biol Chem. 2011;286(4):3079–93.

    PubMed  CAS  Google Scholar 

  117. Warren M, Wang W, Spiden S, et al. A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis. Genesis. 2007;45(1):51–8.

    PubMed  CAS  Google Scholar 

  118. Mao M, Thedens D, Chang B, et al. The podosomal-adaptor protein SH3PXD2B is essential for normal postnatal development. Mamm Genome. 2009;20(8):462–75.

    PubMed  CAS  Google Scholar 

  119. Yang B, Tian C, Zhang Z-g, et al. Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media. PloS ONE. 2011;6(7).

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Acknowledgment

The authors wish to thank Steve Thomas for kindly producing the pathway schematic.

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Conflict of Interest

Hayley E. Tyrer is employed by the MRC Harwell and has received grant support from AstraZeneca and an Action on Hearing Loss Flexi grant 2013.

Michael Crompton declares that he has no conflict of interest.

Mahmood F. Bhutta declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Medical Research Council Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK

    Hayley E. Tyrer, Michael Crompton & Mahmood F. Bhutta

  2. Nuffield Department of Surgical Sciences, University of Oxford, Level 6, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK

    Michael Crompton & Mahmood F. Bhutta

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  1. Hayley E. Tyrer
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  2. Michael Crompton
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Correspondence to Mahmood F. Bhutta.

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Hayley E. Tyrer and Michael Crompton are joint first authors.

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Tyrer, H.E., Crompton, M. & Bhutta, M.F. What Have We Learned from Murine Models of Otitis Media?. Curr Allergy Asthma Rep 13, 501–511 (2013). https://doi.org/10.1007/s11882-013-0360-1

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  • DOI: https://doi.org/10.1007/s11882-013-0360-1

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