Dataset Information

Clarin-2 is essential for hearing by maintaining stereocilia integrity and function.

ABSTRACT: Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2^{clarinet/clarinet} mice (p.Trp4* mutation) exhibit a progressive, early-onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non-syndromic progressive hearing loss. Our in-depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin-2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin-2 leads to loss of mechano-electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin-2 in mammalian hearing, providing insights into the interplay between mechano-electrical transduction and stereocilia maintenance.

SUBMITTER: Dunbar LA

PROVIDER: S-EPMC6728604 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Clarin-2 is essential for hearing by maintaining stereocilia integrity and function.

Dunbar Lucy A LA Patni Pranav P Aguilar Carlos C Mburu Philomena P Corns Laura L Wells Helena Rr HR Delmaghani Sedigheh S Parker Andrew A Johnson Stuart S Williams Debbie D Esapa Christopher T CT Simon Michelle M MM Chessum Lauren L Newton Sherylanne S Dorning Joanne J Jeyarajan Prashanthini P Morse Susan S Lelli Andrea A Codner Gemma F GF Peineau Thibault T Gopal Suhasini R SR Alagramam Kumar N KN Hertzano Ronna R Dulon Didier D Wells Sara S Williams Frances M FM Petit Christine C Dawson Sally J SJ Brown Steve Dm SD Marcotti Walter W El-Amraoui Aziz A Bowl Michael R MR

EMBO molecular medicine 20190826 9

Hearing relies on mechanically gated ion channels present in the actin-rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound-receptive structure is limited. Utilizing a large-scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2<sup>clarinet/clarinet</sup> mice (p.Trp4* mutation) exhibit a progressive, early-on ...[more]

PMID: 31448880

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Project description:AimsNuclear envelope integrity is essential for the compartmentalization of the nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope (NE) and associated proteins are the second highest cause of familial dilated cardiomyopathy. One such NE protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in the heart remains poorly understood.Methods and resultsWe generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or in adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue, and cellular analyses. High-resolution episcopic microscopy was used for three-dimensional reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided a physiological assessment of Lem2 iCKO adult mice. We found that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age.ConclusionsOur data suggest that Lem2 is critical for integrity at the nascent NE in foetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established NE and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general.

Dataset Information

Clarin-2 is essential for hearing by maintaining stereocilia integrity and function.

Publications

Clarin-2 is essential for hearing by maintaining stereocilia integrity and function.

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