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

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 stereo...

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Bibliographic Details
Published inHearing research Vol. 304; pp. 41 - 48
Main Authors Watson, Claire J., Tempel, Bruce L.
Format Journal Article
LanguageEnglish
Published Elsevier B.V 01.10.2013
Subjects
JAX
ahl
IHC
OHC
ENU
MFE
MUT
SPL
ABR
dfw
SNP
ANOVA
Ca2
HET
SEM
MET
WT
dB
PMCA
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Summary: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. •We characterize a new Atp2b2 null deafwaddler allele, dfwi5.•Mice lacking PMCA2 have abnormal stereocilia morphology.•Atp2b2 and Cdh23 interact strongly to cause broad frequency hearing loss.•A second locus interacts with Atp2b2 and modifies hearing loss in +/dfwi5.
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ISSN:0378-5955
1878-5891
DOI:10.1016/j.heares.2013.06.003