Eya4-deficient mice are a model for heritable otitis media
Frederic F.S. Depreux, Keith Darrow, David A. Conner, Roland D. Eavey, M. Charles Liberman, Christine E. Seidman, J.G. Seidman
Frederic F.S. Depreux, Keith Darrow, David A. Conner, Roland D. Eavey, M. Charles Liberman, Christine E. Seidman, J.G. Seidman
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Research Article

Eya4-deficient mice are a model for heritable otitis media

Abstract

Otitis media is an extremely common pediatric inflammation of the middle ear that often causes pain and diminishes hearing. Vulnerability to otitis media is due to eustachian tube dysfunction as well as other poorly understood factors, including genetic susceptibility. As EYA4 mutations cause sensorineural hearing loss in humans, we produced and characterized Eya4-deficient (Eya4–/–) mice, which had severe hearing deficits. In addition, all Eya4–/– mice developed otitis media with effusion. Anatomic studies revealed abnormal middle ear cavity and eustachian tube dysmorphology; thus, Eya4 regulation is critical for the development and function of these structures. We suggest that some human otitis media susceptibility reflects underlying genetic predisposition in genes like EYA4 that regulate middle ear and eustachian tube anatomy.

Authors

Frederic F.S. Depreux, Keith Darrow, David A. Conner, Roland D. Eavey, M. Charles Liberman, Christine E. Seidman, J.G. Seidman

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Figure 3

Comparison of postnatal middle ear cavitation in wild-type (+/+) and Eya4–/– (–/–) mice.

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Comparison of postnatal middle ear cavitation in wild-type (+/+) and Eya...
(A) Six-day-old mice (n = 6, each genotype) had no middle ear effusions. Mesenchymal cells (black arrows) are found in the middle ear cavity, but the middle ear space (red arrows) is visible. Co, cochlea. Scale bars: 200 μm. (B) At days 11 and 12 (n = 3 mice of each genotype), mesenchymal cells (black arrows) have largely disappeared from the middle ear cavity of wild-type mice, but a few cells remain around the ossicles. M, malleus. Many more mesenchymal cells and collagen (asterisks), a by-product of mesenchyme regression, are present in the MECs of Eya4–/– mice than in wild-type mice. See magnified inset (scale bars: 200 μm) showing mucoperiosteum and mesenchyme regression. The marked inward bulging of tympanic membrane in Eya4–/– mice correlated with tympanic membrane retraction that was visible through the external auditory canal (EAC). Scale bar: 40 μm. (C) At days 14–16 (n = 5 for each genotype), some collagen (black asterisks) remains in both genotypes, but Eya4–/– mice also show a hyperplastic mucosa (red asterisk) with inflammation. The opening of the eustachian tube (ET) is indicated (arrowheads). Inset shows a polyp (red arrowhead) and numerous inflammatory cells (black arrow) found in some Eya4–/– mice.