ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 34 citations in OpenAlex.
- Bayesian-Steered Structure Prediction of Mechanical Biomolecules Using Twisted Diffusion.bioRxiv : the preprint server for biology · 2026Article
- The Role of Calcium Signaling in Sensorineural Hearing Loss.International journal of medical sciences · 2025Review
- Current approaches for Usher syndrome disease models and developing therapies.Frontiers in cell and developmental biology · 2025Review
- Article
- Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.Nature communications · 2023Article
- Usher Syndrome: Genetics of a Human Ciliopathy.International journal of molecular sciences · 2021Review
- Crystal structure of the nonclassical cadherin-17 N-terminus and implications for its adhesive binding mechanism.Acta crystallographica. Section F, Structural biology communications · 2021Article
- Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy.Frontiers in genetics · 2020Review
- A Mechanically Weak Extracellular Membrane-Adjacent Domain Induces Dimerization of Protocadherin-15.Biophysical journal · 2018Article
- Zooming in on Cadherin-23: Structural Diversity and Potential Mechanisms of Inherited Deafness.Structure (London, England : 1993) · 2018Article
- Beyond Cell-Cell Adhesion: Sensational Cadherins for Hearing and Balance.Cold Spring Harbor perspectives in biology · 2018Review
- Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15.Biochemistry · 2018Article
- Functional Analysis of the Transmembrane and Cytoplasmic Domains of Pcdh15a in Zebrafish Hair Cells.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- A Partial Calcium-Free Linker Confers Flexibility to Inner-Ear Protocadherin-15.Structure (London, England : 1993) · 2017Article
- Using thermal scanning assays to test protein-protein interactions of inner-ear cadherins.PloS one · 2017Article
- Application of Mouse Models to Research in Hearing and Balance.Journal of the Association for Research in Otolaryngology : JARO · 2016Review
- Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy.eLife · 2016Article
- Shot and Patronin polarise microtubules to direct membrane traffic and biogenesis of microvilli in epithelia.Journal of cell science · 2016Article
- The molecules that mediate sensory transduction in the mammalian inner ear.Current opinion in neurobiology · 2015Review
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Authors and funding
14 authors at 6 institutions in 2 countries.
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Abstract
In hair cells of the inner ear, sound or head movement increases tension in fine filaments termed tip links, which in turn convey force to mechanosensitive ion channels to open them. Tip links are formed by a tetramer of two cadherin proteins: protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which have 11 and 27 extracellular cadherin (EC) repeats, respectively. Mutations in either protein cause inner ear disorders in mice and humans. We showed recently that these two cadherins bind tip-to-tip in a "handshake" mode that involves the EC1 and EC2 repeats of both proteins. However, a paucity of appropriate animal models has slowed our understanding both of the interaction and of how mutations of residues within the predicted interface compromise tip link integrity. Here, we present noddy, a new mouse model for hereditary deafness. Identified in a forward genetic screen, noddy homozygotes lack inner ear function. Mapping and sequencing showed that noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of PCDH15. Residue I108 interacts with CDH23 EC2 in the handshake and its mutation impairs the interaction in vitro. The noddy mutation allowed us to determine the consequences of blocking the handshake in vivo: tip link formation and bundle morphology are disrupted, and mechanotransduction channels fail to remain open at rest. These results offer new insights into the interaction between PCDH15 and CDH23 and help explain the etiology of human deafness linked to mutations in the tip-link interface.
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