SUMMARY Hair cells are mechanosensors for the perception of sound, acceleration and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the TARPs of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cells mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.
Deafness is the most common form of sensory impairment in humans and is frequently caused by single gene mutations. Interestingly, different mutations in a gene can cause syndromic and nonsyndromic forms of deafness, as well as progressive and age-related hearing loss. We provide here an explanation for the phenotypic variability associated with mutations in the cadherin 23 gene (CDH23). CDH23 null alleles cause deaf-blindness (Usher syndrome type 1D; USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12). In a forward genetic screen, we have identified salsa mice, which suffer from hearing loss due to a Cdh23 missense mutation modeling DFNB12. In contrast to waltzer mice, which carry a CDH23 null allele mimicking USH1D, hair cell development is unaffected in salsa mice. Instead, tip links, which are thought to gate mechanotransduction channels in hair cells, are progressively lost. Our findings suggest that DFNB12 belongs to a new class of disorder that is caused by defects in tip links. We propose that mutations in other genes that cause USH1 and nonsyndromic deafness may also have distinct effects on hair cell development and function.cadherin 23 ͉ Cdh23 ͉ Usher syndrome ͉ progressive hearing loss
The cadherin superfamily encodes more than 100 receptors with diverse functions in tissue development and homeostasis. Classical cadherins mediate adhesion by binding interactions that depend on their N-terminal extracellular cadherin (EC) domains, which swap Nterminal β-strands. Sequence alignments suggest that the strandswap binding mode is not commonly used by functionally divergent cadherins. Here, we have determined the structure of the EC1-EC2 domains of cadherin 23 (CDH23), which binds to protocadherin 15 (PCDH15) to form tip links of mechanosensory hair cells. Unlike classical cadherins, the CDH23 N terminus contains polar amino acids that bind Ca 2+ . The N terminus of PCDH15 also contains polar amino acids. Mutations in polar amino acids within EC1 of CDH23 and PCDH15 abolish interaction between the two cadherins. PCDH21 and PCDH24 contain similarly charged N termini, suggesting that a subset of cadherins share a common interaction mechanism that differs from the strand-swap binding mode of classical cadherins.T he organization of cells into tissues and organs depends on cadherin molecules that regulate such diverse processes as cell adhesion, synapse formation, and the development and function of sensory cells in the inner ear and retina (1-4). The defining feature of the cadherin superfamily is the extracellular cadherin (EC) domain, which occurs in varying repetitions in all cadherins. Based on sequence homology and domain structure, cadherins are divided into subfamilies including the classical cadherins, desmosomal cadherins, seven transmembrane cadherins, and protocadherins. Classical cadherins and desmosomal cadherins are the best-studied superfamily members and have well-documented roles in mediating cell adhesion and the formation of desmosomes, respectively (1-4). The function and adhesive properties of other cadherin superfamily members are less well studied.Crystallographic and biochemical studies have provided insights into the structure of cadherin extracellular domains and the mechanism that mediates adhesion between classical cadherins (5-13). The EC domain forms a protein module of the Ig-like fold consisting of seven β-strands that are arranged as two opposed β-sheets. The Nand C termini reside on opposite ends of the EC domain, facilitating the formation of tandem repeats. The connections between successive EC domains are rigidified by coordination of three Ca 2+ ions, which is mediated by amino acids that are conserved in all cadherins (5,9,14). Adhesion specificity resides in the EC1 domains. The crystallographic structures show that the adhesive binding interface is formed by "swapping" of the amino-terminal β-strands of opposite EC1 domains, whereby the strand of one monomer replaces the strand of the other. Critical for this interaction are the side chains of conserved Trp residues, which fit into hydrophobic pockets on the EC1 domain of the binding partner (5,8,10).Recent findings suggest that the formation of cadherin adhesion complexes is a multistep process, where cadherins ...
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