Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells

Söllner, Christian; Rauch, Gerd-Jörg; Siemens, Jan; Geisler, Robert; Schuster, Stephan C.; Müller, Ulrich; Nicolson, Teresa

doi:10.1038/nature02484

Cited by 315 publications

(265 citation statements)

References 29 publications

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“…The striking dichotomy that we observed in the lengths of tip links both in two-dimensional projection images and in three-dimensional tomographic reconstructions is also apparent in published images (Zhao et al 1996;Sollner et al 2004). Variations in tip-link dimensions cannot be attributed to tissue shrinkage, for in some instances long and short links coexisted in the same hair bundle.…”

Section: Organization Of Tip Linkssupporting

confidence: 66%

“…The tip link may consist of glycosylated protein, for polycationic compounds label it (Neugebauer and Thurm 1987;Tsuprun and Santi 2000), and in avian preparations, it is severed by proteases only after deglycosylation (Kachar et al 2000). Genetic and immunological evidence localizes cadherin 23 to the tip link Sollner et al 2004), where it evidently constitutes the structure's upper two thirds (Kazmierczak et al 2007). The balance of the link is thought to consist of protocadherin 15 (Ahmed et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Three-dimensional Architecture of Hair-bundle Linkages Revealed by Electron-microscopic Tomography

Auer

Koster

Ziese

et al. 2008

JARO

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The senses of hearing and balance rest upon mechanoelectrical transduction by the hair bundles of hair cells in the inner ear. Located at the apical cellular surface, each hair bundle comprises several tens of stereocilia and a single kinocilium that are interconnected by extracellular proteinaceous links. Using electron-microscopic tomography of bullfrog saccular sensory epithelia, we examined the three-dimensional structures of basal links, kinociliary links, and tip links. We observed significant differences in the appearances and dimensions of these three structures and found two distinct populations of tip links suggestive of the involvement of different proteins, splice variants, or protein-protein interactions. We noted auxiliary links connecting the upper portions of tip links to the taller stereocilia. Tip links and auxiliary links show a tendency to adopt a globular conformation when disconnected from the membrane surface.

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Section: Organization Of Tip Linkssupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Three-dimensional Architecture of Hair-bundle Linkages Revealed by Electron-microscopic Tomography

Auer

Koster

Ziese

et al. 2008

JARO

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“…The present study shows that null mutations in Cdh23 lead to profound deficits (v 2J , Table 2). Cdh23 has been reported to be a component of tip links in sensory hair cells Sollner et al, 2004); however, more recent reports suggest that Cdh23 is associated with transient lateral links in the developing hair bundles of cochlear sensory cells (Michel et al 2005;Lagziel et al 2005). Interestingly, +/lc is maintained on a C57 Â CBA background, and both of these strains (C57BL/6J and CBA/CaJ) have normal VsEPs up to at least 190 days old.…”

Section: Discussionmentioning

confidence: 97%

A Quantitative Survey of Gravity Receptor Function in Mutant Mouse Strains

Jones

Johnson

et al. 2005

JARO

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The purpose of this research was to identify vestibular deficits in mice using linear vestibular evoked potentials (VsEPs). VsEP thresholds, peak latencies, and peak amplitudes from 24 strains with known genetic mutations and 6 inbred background strains were analyzed and descriptive statistics generated for each strain. Response parameters from mutant homozygotes were compared with heterozygote and/or background controls and all strain averages were contrasted to normative ranges. Homozygotes of the following recessive mutations had absent VsEPs at the ages tested: Espn je , Atp2b2 dfw-2J , Spnb4 qv-lnd2J , Spnb4 qv-3J , Myo7a sh1 , Tmie sr , Myo6 sv , jc, Pcdh15 av-J , Pcdh15 av-2J , Pcdh15 av-3J , Cdh23 v-2J , Sans js , hr, Kcne1 pkr , and Pou3f4 del . These results suggest profound gravity receptor deficits for these homozygotes, which is consistent with the structural deficits that have been documented for many of these strains. Homozygotes of Catna2 cdf , Grid2 ho4J , Wnt1 sw , qk, and Mbp shi strains and heterozygotes of Grid2 lc had measurable VsEPs but one or more response parameters differed from the respective control group (heterozygote or background strain) or were outside normal ranges. For example, qk and Mbp shi homozygotes showed significantly prolonged latencies consistent with the abnormal myelin that has been described for these strains. Prolonged latencies may suggest deficits in neural conduction; elevated thresholds suggest reduced sensitivity, and reduced amplitudes may be suggestive for reduced neural synchrony. One mutation, Otx1 jv , had all VsEP response parameters within normal limits-an expected finding because the abnormality in Otx1 jv is presumably restricted to the lateral semicircular canal. Interestingly, some heterozygote groups also showed abnormalities in one or more VsEP response parameters, suggesting that vestibular dysfunction, although less severe, may be present in some heterozygous animals.

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“…The protocadherin LKC is associated with contact inhibition of cell proliferation, and has been suggested as a candidate TSG for colon and liver cancer (Okazaki et al, 2002). Mutations in protocadherin 15 as well as CDH23 have also been implicated in Usher syndrome (Bolz et al, 2001;Di et al, 2001;Siemens et al, 2002), as recently demonstrated in a zebrafish model Sollner et al, 2004).…”

Section: Introductionmentioning

confidence: 95%

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Ying

Seng³

et al. 2005

Oncogene

243

288

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Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumorspecific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3 -a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2 0 -deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.

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Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells

Cited by 315 publications

References 29 publications

Three-dimensional Architecture of Hair-bundle Linkages Revealed by Electron-microscopic Tomography

Three-dimensional Architecture of Hair-bundle Linkages Revealed by Electron-microscopic Tomography

A Quantitative Survey of Gravity Receptor Function in Mutant Mouse Strains

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

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