Hair Bundles Are Specialized for ATP Delivery via Creatine Kinase

Shin, Jung Bum; Streijger, Femke; Beynon, Andy J.; Peters, Theo; Gadzala, Laura; McMillen, Debra A.; Bystrom, Cory; Zee, Catharina E.E.M. Van der; Wallimann, Theo; Gillespie, Peter G.

doi:10.1016/j.neuron.2006.12.021

Cited by 114 publications

(138 citation statements)

References 73 publications

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“…Strikingly, approximately one-third of all known deafness genes code for proteins localized to the hair bundle (Raviv et al, 2010), an organelle solely dedicated to mechanoelectrical transduction (Hudspeth, 1989;Gillespie and Walker, 2001). We previously used a peptide mass spectrometry-based strategy to characterize the hair bundle proteome, with the goal to discover novel proteins involved in hearing and deafness (Shin et al, 2007(Shin et al, , 2013. As a result, we identified and quantified Ͼ1100 bundle proteins, many of which were previously unidentified within hair cells.…”

Section: Introductionmentioning

confidence: 99%

A Short Splice Form of Xin-Actin Binding Repeat Containing 2 (XIRP2) Lacking the Xin Repeats Is Required for Maintenance of Stereocilia Morphology and Hearing Function

Francis¹,

Krey

Krystofiak

et al. 2015

J. Neurosci.

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Approximately one-third of known deafness genes encode proteins located in the hair bundle, the sensory hair cell's mechanoreceptive organelle. In previous studies, we used mass spectrometry to characterize the hair bundle's proteome, resulting in the discovery of novel bundle proteins. One such protein is Xin-actin binding repeat containing 2 (XIRP2), an actin-cross-linking protein previously reported to be specifically expressed in striated muscle. Because mutations in other actin-cross-linkers result in hearing loss, we investigated the role of XIRP2 in hearing function. In the inner ear, XIRP2 is specifically expressed in hair cells, colocalizing with actin-rich structures in bundles, the underlying cuticular plate, and the circumferential actin belt. Analysis using peptide mass spectrometry revealed that the bundle harbors a previously uncharacterized XIRP2 splice variant, suggesting XIRP2's role in the hair cell differs significantly from that reported in myocytes. To determine the role of XIRP2 in hearing, we applied clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated genome-editing technology to induce targeted mutations into the mouse Xirp2 gene, resulting in the elimination of XIRP2 protein expression in the inner ear. Functional analysis of hearing in the resulting Xirp2-null mice revealed high-frequency hearing loss, and ultrastructural scanning electron microscopy analyses of hair cells demonstrated stereocilia degeneration in these mice. We thus conclude that XIRP2 is required for long-term maintenance of hair cell stereocilia, and that its dysfunction causes hearing loss in the mouse.

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Section: Introductionmentioning

confidence: 99%

A Short Splice Form of Xin-Actin Binding Repeat Containing 2 (XIRP2) Lacking the Xin Repeats Is Required for Maintenance of Stereocilia Morphology and Hearing Function

Francis¹,

Krey

Krystofiak

et al. 2015

J. Neurosci.

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“…Because stereocilia contain no mitochondria, the PCr-CK system thus plays a critical role in maintaining their supply. The importance of the PCr-CK system has been demonstrated using a CKB-knockout mouse model that preferentially exhibits high-tone hearing loss (7). In the postmortem brains of HD patients, CKB is oxidatively modified and progressively inhibited as the disease advances (8).…”

Section: Introductionmentioning

confidence: 99%

Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease

Lin¹,

Chen²,

Soong³

et al. 2011

J. Clin. Invest.

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“…Ckb knockout mice display HI and vestibular dysfunction. The cytosolic brain isoform of creatine kinase is the most abundant protein after β-actin in the avian utricle hair bundle, as discovered using mass spectrometry (Shin et al, 2007).…”

Section: Deaf Mouse Mutants Not Correlated With Human Hereditary Hearmentioning

confidence: 99%

Mouse models to study inner ear development and hereditary hearing loss

Friedman¹,

Dror²,

Avraham³

2007

Int. J. Dev. Biol.

107

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Hereditary sensorineural hearing loss, derived from inner ear defects, is the most common hereditary disability with a prevalence of 1 in 1000 children, although it can be present in up to 15% of births in isolated communities. The mouse serves as an ideal animal model to identify new deafness-related genes and to study their roles in vivo. This review describes mouse models for genes that have been linked with hearing impairment (HI) in humans. Mutations in several groups of genes have been linked with HI in both mice and humans. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. For example, the roles of collagens and tectorins in the tectorial membrane, as well as the necessity of intact links between the hair cell projections, stereocilia and kinocilia, have been discovered in mice. Accurate endolymph composition and the proteins which participate in its production were found to be crucial for inner ear function, as well as several motor proteins such as prestin and myosins. Two systematic projects, KOMP and EUCOMM, which are currently being carried out to create knockout and conditional mutants for every gene in the mouse genome, promise that many additional deafness-related genes will be identified in the next years, providing models for all forms of human deafness.

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Hair Bundles Are Specialized for ATP Delivery via Creatine Kinase

Cited by 114 publications

References 73 publications

A Short Splice Form of Xin-Actin Binding Repeat Containing 2 (XIRP2) Lacking the Xin Repeats Is Required for Maintenance of Stereocilia Morphology and Hearing Function

A Short Splice Form of Xin-Actin Binding Repeat Containing 2 (XIRP2) Lacking the Xin Repeats Is Required for Maintenance of Stereocilia Morphology and Hearing Function

Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease

Mouse models to study inner ear development and hereditary hearing loss

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