A new Atp2b2 deafwaddler allele, dfwⁱ⁵, interacts strongly with Cdh23 and other auditory modifiers

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• 作者：Claire J. Watson ; Bruce L. Tempel
• 关键词：ABR ; auditory-evoked brainstem response ; ahl ; age-related hearing loss ; ANOVA ; analysis of variance ; Ca2+ ; calcium ; dB ; decibels ; dfw ; deafwaddler ; ENU ; N-ethyl-N-nitrosourea ; HET ; heterozygote ; IHC ; inner hair cell ; JAX ; Jackson Laboratory ; MET ; mechanoe
• 刊名：Hearing Research
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：304
• 期：Complete
• 页码：41-48
• 全文大小：1253 K

文摘

Tight regulation of calcium (Ca²⁺) concentrations in the stereocilia bundles of auditory hair cells of the inner ear is critical to normal auditory transduction. The plasma membrane Ca²⁺ ATPase 2 (PMCA2), encoded by the Atp2b2 gene, is the primary mechanism for clearance of Ca²⁺ from auditory stereocilia, keeping intracellular levels low, and also contributes to maintaining adequate levels of extracellular Ca²⁺ in the endolymph. This study characterizes a novel null Atp2b2 allele, dfwⁱ⁵, by examining cochlear anatomy, vestibular function and auditory physiology in mutant mice. Loss of auditory function in PMCA2 mutants can be attributed to dysregulation of intracellular Ca²⁺ inside the stereocilia bundles. However, extracellular Ca²⁺ ions surrounding the stereocilia are also required for rigidity of cadherin 23, a component of the stereocilia tip-link encoded by the Cdh23 gene. This study further resolves the interaction between Atp2b2 and Cdh23 in a gene dosage and frequency-dependent manner, and finds that low frequencies are significantly affected by the interaction. In?+/dfwⁱ⁵ mice, one mutant copy of Cdh23 is sufficient to cause broad frequency hearing impairment. Additionally, we report another modifying interaction with Atp2b2 on auditory sensitivity, possibly caused by an unidentified hearing loss gene in mice.