Physical and Functional Interaction between Protocadherin 15 and Myosin VIIa in Mechanosensory Hair Cells

Senften, Mathias; Schwander, Martin; Kaźmierczak, Piotr; Lillo, Concepción; Shin, Jung Bum; Hasson, Tama; Géléoc, Gwenaëlle S. G.; Gillespie, Peter G.; Williams, David S.; Holt, Jeffrey R.; Müller, Ulrich

doi:10.1523/jneurosci.4251-05.2006

Cited by 159 publications

(199 citation statements)

References 45 publications

(72 reference statements)

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“…The tissues were embedded in paraffin, sectioned, and stained via routine techniques. Whole-mount surface preparation and staining of neonatal cochleas were performed as described previously (Senften et al, 2006).…”

Section: Histology/immunohistochemistrymentioning

confidence: 99%

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P₂

Herr¹,

Grillet²,

Schwander³

et al. 2007

J. Neurosci.

111

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Hearing requires the transduction of vibrational forces by specialized epithelial cells in the cochlea known as hair cells. The human ear contains a finite number of terminally differentiated hair cells that, once lost by noise-induced damage or toxic insult, can never be regenerated. We report here that sphingosine 1-phosphate (S1P) signaling, mainly via activation of its cognate receptor S1P 2 , is required for the maintenance of vestibular and cochlear hair cells in vivo. Two S1P receptors, S1P 2 and S1P 3 , were found to be expressed in the cochlea by reverse transcription-PCR and in situ hybridization. Mice that are null for both these receptors uniformly display progressive cochlear and vestibular defects with hair cell loss, resulting in complete deafness by 4 weeks of age and, with complete penetrance, balance defects of increasing severity. This study reveals the previously unknown role of S1P signaling in the maintenance of cochlear and vestibular integrity and suggests a means for therapeutic intervention in degenerative hearing loss.

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Section: Histology/immunohistochemistrymentioning

confidence: 99%

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P₂

Herr¹,

Grillet²,

Schwander³

et al. 2007

J. Neurosci.

111

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“…The direct in vitro interactions between the five USH1 proteins (2,(12)(13)(14)(15)(16) and the colocalization of cadherin-23, protocadherin-15, myosin VIIa, and harmonin in the growing hair bundle, along with the common early morphological defect in cochlear hair bundles of mouse mutants defective for any USH1 gene (17), suggest that USH1 proteins cooperate in hair bundle development. It has been proposed that harmonin-b anchors transient fibrous lateral links to the stereocilia actin filaments and that myosin VIIa creates tension on these links (2,16), but the role played by sans is still unknown.…”

mentioning

confidence: 99%

Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

Caberlotto

Michel

Foucher

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

124

178

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The mechanotransducer channels of auditory hair cells are gated by tip-links, oblique filaments that interconnect the stereocilia of the hair bundle. Tip-links stretch from the tips of stereocilia in the short and middle rows to the sides of neighboring, taller stereocilia. They are made of cadherin-23 and protocadherin-15, products of the Usher syndrome type 1 genes USH1D and USH1F, respectively. In this study we address the role of sans, a putative scaffold protein and product of the USH1G gene. In Ush1g −/− mice, the cohesion of stereocilia is disrupted, and both the amplitude and the sensitivity of the transduction currents are reduced. In Ush1g fl/fl Myo15-cre +/− mice, the loss of sans occurs postnatally and the stereocilia remain cohesive. In these mice, there is a decrease in the amplitude of the total transducer current with no loss in sensitivity, and the tips of the stereocilia in the short and middle rows lose their prolate shape, features that can be attributed to the loss of tip-links. Furthermore, stereocilia from these rows undergo a dramatic reduction in length, suggesting that the mechanotransduction machinery has a positive effect on F-actin polymerization. Sans interacts with the cytoplasmic domains of cadherin-23 and protocadherin-15 in vitro and is absent from the hair bundle in mice defective for either of the two cadherins. Because sans localizes mainly to the tips of short-and middle-row stereocilia in vivo, we conclude that it belongs to a molecular complex at the lower end of the tip-link and plays a critical role in the maintenance of this link.auditory mechanoelectrical transduction | Usher syndrome type 1 | deafness | conditional knockout mice | organ of Corti

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“…CDH23 and PCDH15 are components of transient lateral links, kinociliary links, and tip links ( Fig. 1 A) (16)(17)(18)(19)(20), and their cytoplasmic domains bind to protein complexes containing harmonin, MYO7A, and sans (21)(22)(23)(24)(25). Predicted null mutations in murine USH1 genes cause defects in hair bundle development (24,(26)(27)(28)(29)(30)(31)(32)(33)(34), suggesting that USH1 proteins form transmembrane complexes that regulate hair bundle morphogenesis.…”

mentioning

confidence: 99%

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

Schwander

Xiong

Tokita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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

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Physical and Functional Interaction between Protocadherin 15 and Myosin VIIa in Mechanosensory Hair Cells

Cited by 159 publications

References 45 publications

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P₂

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P₂

Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

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Physical and Functional Interaction between Protocadherin 15 and Myosin VIIa in Mechanosensory Hair Cells

Cited by 159 publications

References 45 publications

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P2

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P2

Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

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Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P₂

Sphingosine 1-Phosphate (S1P) Signaling Is Required for Maintenance of Hair Cells Mainly via Activation of S1P₂