The Experts below are selected from a list of 23910 Experts worldwide ranked by ideXlab platform
Karen P. Steel - One of the best experts on this subject based on the ideXlab platform.
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progressive hearing loss and increased susceptibility to noise induced hearing loss in mice carrying a CDH23 but not a myo7a mutation
Jaro-journal of The Association for Research in Otolaryngology, 2004Co-Authors: Ralph H. Holme, Karen P. SteelAbstract:Exposure to intense noise can damage the stereocilia of sensory hair cells in the inner ear. Since stereocilia play a vital role in the transduction of sound from a mechanical stimulus into an electrical one, this pathology is thought to contribute to noise-induced hearing loss. Mice homozygous for null mutations in either the myosin VIIa (Myo7a) or cadherin 23 (CDH23) genes are deaf and have disorganized stereocilia bundles. We show that mice heterozygous for a presumed null allele of CDH23 (CDH23v) have low- and high-frequency hearing loss at 5–6 weeks of age, the high-frequency component of which worsens with increasing age. We also show that noise-induced hearing loss in 11–12-week-old CDH23v heterozygotes is two times greater than for wild-type littermates. Interestingly, these effects are dependent upon the genetic background on which the CDH23v mutation is carried. Noise-induced hearing loss in 11–12-week-old mice heterozygous for a null allele of Myo7a (Myo7a4626SB) is not significantly different from wild-type littermates. CDH23 is the first gene known to cause deafness in the human population to be linked with predisposition to noise-induced hearing loss.
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CDH23 mutations in the mouse are associated with retinal dysfunction but not retinal degeneration.
Experimental eye research, 2003Co-Authors: Richard T. Libby, David S Williams, Junko Kitamoto, Ralph H. Holme, Karen P. SteelAbstract:Mutations in the cadherin 23 gene (CDH23) cause Usher syndrome type 1D in humans, a disease that results in retinitis pigmentosa and deafness. CDH23 is also mutated in the waltzer mouse. In order to determine if the retina of the waltzer mouse undergoes retinal degeneration and to gain insight into the function of cadherin 23 in the retina, we have characterized the anatomy and physiology of retinas of waltzer mouse mutants. Three mutant alleles of CDH23 were examined by histology and electroretinography (ERG). ERGs of the three CDH23 mutant groups revealed two of them to have abnormal retinal function. One allele had a- and b-waves that were only approximately 80% of CDH23 heterozygotes. Another allele had a significantly faster implicit time for both the a- and b-waves of the ERG. No anatomical abnormality was detected in any of the CDH23 mutants by light microscopy. Because the mutant CDH23 phenotype was found to be similar to the previously reported retinal phenotype of Myo7a mutant mice, the orthologue of another Usher syndrome (type 1B) gene, we generated mice that carried mutations in both genes to test for genetic interaction in the retina. No functional interaction between cadherin 23 and myosin VIIa was detected by either microscopy or ERG.
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stereocilia defects in waltzer CDH23 shaker1 myo7a and double waltzer shaker1 mutant mice
Hearing Research, 2002Co-Authors: Ralph H. Holme, Karen P. SteelAbstract:Abstract Mutations in myosin VIIa ( Myo7a ) and cadherin 23 ( CDH23 ) cause deafness in shaker1 ( sh1 ) and waltzer ( v ) mouse mutants respectively. In humans, mutations in these genes cause Usher’s syndrome type 1B and D respectively, as well as certain forms of non-syndromic deafness. Examination of the organ of Corti from shaker1 and waltzer mice has shown that these genes are required for the proper organisation of hair cell stereocilia. Here we show that at embryonic day 18.5, the outer hair cells of CDH23 v homozygote mutant mice appear immature, projecting fewer recognisable stereocilia than heterozygote controls, and by post-natal day (P) 4 their stereocilia are arranged in a disorganised pattern rather than in the regular ‘V’-shape seen in heterozygotes. Inner hair cell stereocilia are also disorganised in CDH23 v mutant homozygotes. Myo7a was expressed normally in the hair cells of P0 CDH23 v2J mutants demonstrating that cadherin 23 is not required for Myo7a expression at this stage. No stereocilia defects were observed in P4 CDH23 v /Myo7a 4626SB double heterozygotes (+/ CDH23 v +/ Myo7a 4626SB ) and neither the CDH23 v nor Myo7a 4626SB homozygote phenotypes were affected by the presence of one mutant copy of Myo7a or CDH23 respectively. The hair cell phenotype of double homozygote mutant mice did not differ from single Myo7a 4626SB homozygote mutants. Finally, we found no significant correlation between loss of hearing and double heterozygosity for mutations in CDH23 and Myo7a in mice aged between 7.5 and 10 months. These findings suggest that CDH23 and Myo7a are both required for establishing and/or maintaining the proper organisation of the stereocilia bundle and that they do not genetically interact to affect this process nor to cause age-related hearing loss.
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Stereocilia defects in waltzer (CDH23), shaker1 (Myo7a) and double waltzer/shaker1 mutant mice.
Hearing research, 2002Co-Authors: Ralph H. Holme, Karen P. SteelAbstract:Mutations in myosin VIIa (Myo7a) and cadherin 23 (CDH23) cause deafness in shaker1 (sh1) and waltzer (v) mouse mutants respectively. In humans, mutations in these genes cause Usher's syndrome type 1B and D respectively, as well as certain forms of non-syndromic deafness. Examination of the organ of Corti from shaker1 and waltzer mice has shown that these genes are required for the proper organisation of hair cell stereocilia. Here we show that at embryonic day 18.5, the outer hair cells of CDH23(v) homozygote mutant mice appear immature, projecting fewer recognisable stereocilia than heterozygote controls, and by post-natal day (P) 4 their stereocilia are arranged in a disorganised pattern rather than in the regular 'V'-shape seen in heterozygotes. Inner hair cell stereocilia are also disorganised in CDH23(v) mutant homozygotes. Myo7a was expressed normally in the hair cells of P0 CDH23(v2J) mutants demonstrating that cadherin 23 is not required for Myo7a expression at this stage. No stereocilia defects were observed in P4 CDH23(v)/Myo7a(4626SB) double heterozygotes (+/CDH23(v) +/Myo7a(4626SB)) and neither the CDH23(v) nor Myo7a(4626SB) homozygote phenotypes were affected by the presence of one mutant copy of Myo7a or CDH23 respectively. The hair cell phenotype of double homozygote mutant mice did not differ from single Myo7a(4626SB) homozygote mutants. Finally, we found no significant correlation between loss of hearing and double heterozygosity for mutations in CDH23 and Myo7a in mice aged between 7.5 and 10 months. These findings suggest that CDH23 and Myo7a are both required for establishing and/or maintaining the proper organisation of the stereocilia bundle and that they do not genetically interact to affect this process nor to cause age-related hearing loss.
Ralph H. Holme - One of the best experts on this subject based on the ideXlab platform.
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progressive hearing loss and increased susceptibility to noise induced hearing loss in mice carrying a CDH23 but not a myo7a mutation
Jaro-journal of The Association for Research in Otolaryngology, 2004Co-Authors: Ralph H. Holme, Karen P. SteelAbstract:Exposure to intense noise can damage the stereocilia of sensory hair cells in the inner ear. Since stereocilia play a vital role in the transduction of sound from a mechanical stimulus into an electrical one, this pathology is thought to contribute to noise-induced hearing loss. Mice homozygous for null mutations in either the myosin VIIa (Myo7a) or cadherin 23 (CDH23) genes are deaf and have disorganized stereocilia bundles. We show that mice heterozygous for a presumed null allele of CDH23 (CDH23v) have low- and high-frequency hearing loss at 5–6 weeks of age, the high-frequency component of which worsens with increasing age. We also show that noise-induced hearing loss in 11–12-week-old CDH23v heterozygotes is two times greater than for wild-type littermates. Interestingly, these effects are dependent upon the genetic background on which the CDH23v mutation is carried. Noise-induced hearing loss in 11–12-week-old mice heterozygous for a null allele of Myo7a (Myo7a4626SB) is not significantly different from wild-type littermates. CDH23 is the first gene known to cause deafness in the human population to be linked with predisposition to noise-induced hearing loss.
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CDH23 mutations in the mouse are associated with retinal dysfunction but not retinal degeneration.
Experimental eye research, 2003Co-Authors: Richard T. Libby, David S Williams, Junko Kitamoto, Ralph H. Holme, Karen P. SteelAbstract:Mutations in the cadherin 23 gene (CDH23) cause Usher syndrome type 1D in humans, a disease that results in retinitis pigmentosa and deafness. CDH23 is also mutated in the waltzer mouse. In order to determine if the retina of the waltzer mouse undergoes retinal degeneration and to gain insight into the function of cadherin 23 in the retina, we have characterized the anatomy and physiology of retinas of waltzer mouse mutants. Three mutant alleles of CDH23 were examined by histology and electroretinography (ERG). ERGs of the three CDH23 mutant groups revealed two of them to have abnormal retinal function. One allele had a- and b-waves that were only approximately 80% of CDH23 heterozygotes. Another allele had a significantly faster implicit time for both the a- and b-waves of the ERG. No anatomical abnormality was detected in any of the CDH23 mutants by light microscopy. Because the mutant CDH23 phenotype was found to be similar to the previously reported retinal phenotype of Myo7a mutant mice, the orthologue of another Usher syndrome (type 1B) gene, we generated mice that carried mutations in both genes to test for genetic interaction in the retina. No functional interaction between cadherin 23 and myosin VIIa was detected by either microscopy or ERG.
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stereocilia defects in waltzer CDH23 shaker1 myo7a and double waltzer shaker1 mutant mice
Hearing Research, 2002Co-Authors: Ralph H. Holme, Karen P. SteelAbstract:Abstract Mutations in myosin VIIa ( Myo7a ) and cadherin 23 ( CDH23 ) cause deafness in shaker1 ( sh1 ) and waltzer ( v ) mouse mutants respectively. In humans, mutations in these genes cause Usher’s syndrome type 1B and D respectively, as well as certain forms of non-syndromic deafness. Examination of the organ of Corti from shaker1 and waltzer mice has shown that these genes are required for the proper organisation of hair cell stereocilia. Here we show that at embryonic day 18.5, the outer hair cells of CDH23 v homozygote mutant mice appear immature, projecting fewer recognisable stereocilia than heterozygote controls, and by post-natal day (P) 4 their stereocilia are arranged in a disorganised pattern rather than in the regular ‘V’-shape seen in heterozygotes. Inner hair cell stereocilia are also disorganised in CDH23 v mutant homozygotes. Myo7a was expressed normally in the hair cells of P0 CDH23 v2J mutants demonstrating that cadherin 23 is not required for Myo7a expression at this stage. No stereocilia defects were observed in P4 CDH23 v /Myo7a 4626SB double heterozygotes (+/ CDH23 v +/ Myo7a 4626SB ) and neither the CDH23 v nor Myo7a 4626SB homozygote phenotypes were affected by the presence of one mutant copy of Myo7a or CDH23 respectively. The hair cell phenotype of double homozygote mutant mice did not differ from single Myo7a 4626SB homozygote mutants. Finally, we found no significant correlation between loss of hearing and double heterozygosity for mutations in CDH23 and Myo7a in mice aged between 7.5 and 10 months. These findings suggest that CDH23 and Myo7a are both required for establishing and/or maintaining the proper organisation of the stereocilia bundle and that they do not genetically interact to affect this process nor to cause age-related hearing loss.
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Stereocilia defects in waltzer (CDH23), shaker1 (Myo7a) and double waltzer/shaker1 mutant mice.
Hearing research, 2002Co-Authors: Ralph H. Holme, Karen P. SteelAbstract:Mutations in myosin VIIa (Myo7a) and cadherin 23 (CDH23) cause deafness in shaker1 (sh1) and waltzer (v) mouse mutants respectively. In humans, mutations in these genes cause Usher's syndrome type 1B and D respectively, as well as certain forms of non-syndromic deafness. Examination of the organ of Corti from shaker1 and waltzer mice has shown that these genes are required for the proper organisation of hair cell stereocilia. Here we show that at embryonic day 18.5, the outer hair cells of CDH23(v) homozygote mutant mice appear immature, projecting fewer recognisable stereocilia than heterozygote controls, and by post-natal day (P) 4 their stereocilia are arranged in a disorganised pattern rather than in the regular 'V'-shape seen in heterozygotes. Inner hair cell stereocilia are also disorganised in CDH23(v) mutant homozygotes. Myo7a was expressed normally in the hair cells of P0 CDH23(v2J) mutants demonstrating that cadherin 23 is not required for Myo7a expression at this stage. No stereocilia defects were observed in P4 CDH23(v)/Myo7a(4626SB) double heterozygotes (+/CDH23(v) +/Myo7a(4626SB)) and neither the CDH23(v) nor Myo7a(4626SB) homozygote phenotypes were affected by the presence of one mutant copy of Myo7a or CDH23 respectively. The hair cell phenotype of double homozygote mutant mice did not differ from single Myo7a(4626SB) homozygote mutants. Finally, we found no significant correlation between loss of hearing and double heterozygosity for mutations in CDH23 and Myo7a in mice aged between 7.5 and 10 months. These findings suggest that CDH23 and Myo7a are both required for establishing and/or maintaining the proper organisation of the stereocilia bundle and that they do not genetically interact to affect this process nor to cause age-related hearing loss.
Qing Yin Zheng - One of the best experts on this subject based on the ideXlab platform.
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tauroursodeoxycholic acid prevents hearing loss and hair cell death in CDH23erl erl mice
Neuroscience, 2016Co-Authors: J. Yuan, Qing Yin Zheng, S. EntenmanAbstract:Sensorineural hearing loss has long been the subject of experimental and clinical research for many years. The recently identified novel mutation of the Cadherin23 (CDH23) gene, CDH23(erl/erl), was proven to be a mouse model of human autosomal recessive nonsyndromic deafness (DFNB12). Tauroursodeoxycholic acid (TUDCA), a taurine-conjugated bile acid, has been used in experimental research and clinical applications related to liver disease, diabetes, neurodegenerative diseases, and other diseases associated with apoptosis. Because hair cell apoptosis was implied to be the cellular mechanism leading to hearing loss in CDH23(erl/erl) mice (erl mice), this study investigated TUDCA's otoprotective effects in erl mice: preventing hearing impairment and protecting against hair cell death. Our results showed that systemic treatment with TUDCA significantly alleviated hearing loss and suppressed hair cell death in erl mice. Additionally, TUDCA inhibited apoptotic genes and caspase-3 activation in erl mouse cochleae. The data suggest that TUDCA could be a potential therapeutic agent for human DFNB12.
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Tauroursodeoxycholic acid prevents hearing loss and hair cell death in CDH23erl/erl mice
Neuroscience, 2015Co-Authors: J. Yuan, S. Entenman, Qing Yin ZhengAbstract:Sensorineural hearing loss has long been the subject of experimental and clinical research for many years. The recently identified novel mutation of the Cadherin23 (CDH23) gene, CDH23(erl/erl), was proven to be a mouse model of human autosomal recessive nonsyndromic deafness (DFNB12). Tauroursodeoxycholic acid (TUDCA), a taurine-conjugated bile acid, has been used in experimental research and clinical applications related to liver disease, diabetes, neurodegenerative diseases, and other diseases associated with apoptosis. Because hair cell apoptosis was implied to be the cellular mechanism leading to hearing loss in CDH23(erl/erl) mice (erl mice), this study investigated TUDCA's otoprotective effects in erl mice: preventing hearing impairment and protecting against hair cell death. Our results showed that systemic treatment with TUDCA significantly alleviated hearing loss and suppressed hair cell death in erl mice. Additionally, TUDCA inhibited apoptotic genes and caspase-3 activation in erl mouse cochleae. The data suggest that TUDCA could be a potential therapeutic agent for human DFNB12.
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Otoprotective effects of erythropoietin on CDH23erl/erl mice.
Neuroscience, 2013Co-Authors: Fengchan Han, Tihua Zheng, Xin Zhao, Qing Yin ZhengAbstract:Abstract The CDH23 erl/erl mice are a novel mouse model for DFNB12 and are characterized by progressive hearing loss. In this study, erythropoietin (EPO) was given to the CDH23 erl/erl mice by intraperitoneal injection every other day from P7 for 7 weeks. Phosphate-buffered saline-treated or untreated CDH23 erl/erl mice were used as controls. Auditory-evoked brainstem response (ABR) thresholds and distortion product oto-acoustic emission (DPOAE) were measured in the mouse groups at the age of 4, 6 and 8 weeks. The results show that EPO can significantly decrease the ABR thresholds in the CDH23 erl/erl mice as compared with those of the untreated mice at stimulus frequencies of click, 8-, 16- and 32-kHz at three time points. Meanwhile, DPOAE amplitudes in the EPO-treated CDH23 erl/erl mouse group were significantly higher than those of the untreated groups at f2 frequency of 15383 Hz at the three time points. Furthermore, the mean percentage of outer hair cell loss at middle through basal turns of cochleae was significantly lower in EPO-treated CDH23 erl/erl mice than in the untreated mice ( P 0.05). This is the first report that EPO acts as an otoprotectant in a DFNB12 mouse model with progressive hearing loss.
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digenic inheritance of deafness caused by 8j allele of myosin viia and mutations in other usher i genes
Human Molecular Genetics, 2012Co-Authors: Qing Yin Zheng, John D. Scarborough, Ye Zheng, Dongseok Choi, Peter G. GillespieAbstract:double heterozygous mice alsoshowed elevated hearing loss, suggestingPcdh15–Ush1g epistasis. While we readily detected MYO7A,USH1C, CDH23 and PCDH15 using mass spectrometry of purified chick utricle hair bundles, we did notdetect USH1G. Consistent with that observation, Ush1g microarray signals were much lower in chick cochleathan those of Myo7a, Ush1c, CDH23 and Pcdh15 and were not detected in the chick utricle. These experimentsconfirm the importance of MYO7A for the development and maintenance of bundle function and support thesuggestion that MYO7A, USH1G (Sans) and CDH23 form the upper tip-link complex in adult mice, likely incombination with USH1C (harmonin). MYO7A, USH1G and PCDH15 may form another complex in stereocilia.USH1G may be a limiting factor in both complexes.
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a mutation in the CDH23 gene causes age related hearing loss in CDH23 nmf308 nmf308 mice
Gene, 2012Co-Authors: Siwei Liu, Hong-liang Zhu, Shaoli Cheng, Qing Yin ZhengAbstract:Cadherin 23 (CDH23) is an important constituent of the hair cell tip link in the organ of Corti. Mutations in CDH23 are associated with age-related hearing loss (AHL). In this study, we proposed that the CDH23(nmf308/nmf308) mice with progressive hair cell loss had specific morphological changes and suffered a base to apex gradient and age-related hearing loss, and that mutations in CDH23 were linked to AHL. The CDH23(nmf308/nmf308) mice produced by the N-nitrosourea (ENU) mutagenesis program were used as an animal model to study AHL and progressive hair cell loss. RT-PCR was performed to confirm the CDH23 mutation in CDH23(nmf308/nmf308) mice and genetic analysis was used to map the specific mutation site. Distortion product otoacoustic emission (DPOAE) assay and acoustic brainstem evoked response (ABR) threshold analysis were carried out to evaluate the AHL. Cochlear histology was examined with scanning electron microscope (SEM) and transmission electron microscope (TEM), as well as the nuclear labeling by propidium iodide staining; terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and caspase-3 activities were examined to evaluate cell apoptosis. Genetic mapping identified the candidate gene linking AHL in CDH23(nmf308/nmf308) mice as CDH23. A mutation in exon3 (63 T>C) was screened as compared with the sequence of the same position of the gene from B6 (+/+) mice. The cochleae outer hair cells were reduced from 5-10% at one month to 100% at three months in the basal region. DPOAE and ABR exhibited an increasing threshold at high frequencies (≥16kHz) from one month of age. Morphological and cellular analysis showed that CDH23(nmf308/nmf308) mice exhibited a time course of histological alterations and cell apoptosis of outer hair cells. Our results suggest that the CDH23 mutation may be harmful to the stereociliary tip link and cause the hair cell apoptosis. Due to the same CDH23 mutations in human subjects with presbycusis (Petit et al., 2001; Zheng et al., 2005), the CDH23(nmf308/nmf308) mouse is an excellent animal model for investigating the mechanisms involved in human AHL.
Hanshenrik M Dahl - One of the best experts on this subject based on the ideXlab platform.
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an enu induced mutation of CDH23 causes congenital hearing loss but no vestibular dysfunction in mice
American Journal of Pathology, 2011Co-Authors: Shehnaaz S M Manji, Kerry A Miller, Louise H Williams, Lotte Andreasen, Maria Siboe, Elizabeth Rose, Michael J Kuiper, Hanshenrik M Dahl, Melanie BahloAbstract:Mutations in the human cadherin 23 (CDH23) gene cause deafness, neurosensory, autosomal recessive 12 (DFNB12) nonsyndromic hearing loss or Usher syndrome, type 1D (characterized by hearing impairment, vestibular dysfunction, and visual impairment). Reported waltzer mouse strains each harbor a CDH23-null mutation and present with hearing loss and vestibular dysfunction. Two additional CDH23 mouse mutants, salsa and erlong, each carry a homozygous CDH23 missense mutation and have progressive hearing loss. We report the identification of a novel mouse strain, jera, with inherited hearing loss caused by an N-ethyl-N-nitrosourea–induced c.7079T>A mutation in the CDH23 gene. The mutation generates a missense change, p.V2360E, in CDH23. Affected mice have profound sensorineural deafness, with no vestibular dysfunction. The p.V2360E mutation is semidominant because heterozygous mice have milder and more progressive hearing loss in advanced age. The mutation affects a highly conserved Ca2+-binding motif in extracellular domain 22, thought to be important for CDH23 structure and dimerization. Molecular modeling suggests that the CDH23V2360E/V2360E mutation alters the structural conformation of the protein and affects Ca2+-binding properties. Similar to salsa mice, but in contrast to waltzer mice, hair bundle development is normal in jera and hearing loss appears to be due to the loss of tip links. Thus, jera is a novel mouse model for DFNB12.
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an enu induced mutation of CDH23 causes congenital hearing loss but no vestibular dysfunction in mice
American Journal of Pathology, 2011Co-Authors: Shehnaaz S M Manji, Kerry A Miller, Louise H Williams, Lotte Andreasen, Maria Siboe, Elizabeth Rose, Michael J Kuiper, Hanshenrik M Dahl, Melanie BahloAbstract:Mutations in the human cadherin 23 (CDH23) gene cause deafness, neurosensory, autosomal recessive 12 (DFNB12) nonsyndromic hearing loss or Usher syndrome, type 1D (characterized by hearing impairment, vestibular dysfunction, and visual impairment). Reported waltzer mouse strains each harbor a CDH23-null mutation and present with hearing loss and vestibular dysfunction. Two additional CDH23 mouse mutants, salsa and erlong, each carry a homozygous CDH23 missense mutation and have progressive hearing loss. We report the identification of a novel mouse strain, jera, with inherited hearing loss caused by an N-ethyl-N-nitrosourea–induced c.7079T>A mutation in the CDH23 gene. The mutation generates a missense change, p.V2360E, in CDH23. Affected mice have profound sensorineural deafness, with no vestibular dysfunction. The p.V2360E mutation is semidominant because heterozygous mice have milder and more progressive hearing loss in advanced age. The mutation affects a highly conserved Ca2+-binding motif in extracellular domain 22, thought to be important for CDH23 structure and dimerization. Molecular modeling suggests that the CDH23V2360E/V2360E mutation alters the structural conformation of the protein and affects Ca2+-binding properties. Similar to salsa mice, but in contrast to waltzer mice, hair bundle development is normal in jera and hearing loss appears to be due to the loss of tip links. Thus, jera is a novel mouse model for DFNB12.
Ulrich Müller - One of the best experts on this subject based on the ideXlab platform.
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Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010Co-Authors: Andrea Lelli, Piotr Kazmierczak, Ulrich Müller, Yoshiyuki Kawashima, Jeffrey R. HoltAbstract:Tip links are extracellular filaments that connect pairs of hair cell stereocilia and convey tension to mechanosensitive channels. Recent evidence suggests that tip links are formed by calcium-dependent interactions between the N-terminal domains of cadherin-23 (CDH23) and protocadherin-15 (PCDH15). Mutations in either CDH23 or PCDH15 cause deafness in mice and humans, indicating the molecules are required for normal inner ear function. However, there is little physiological evidence to support a direct role for CDH23 and PCDH15 in hair cell mechanotransduction. To investigate the contributions of CDH23 and PCDH15 to mechanotransduction and tip-link formation, we examined outer hair cells of mouse cochleas during development and after chemical disruption of tip links. We found that tip links and mechanotransduction with all the qualitative properties of mature transduction recovered within 24 h after disruption. To probe tip-link formation, we measured transduction currents after extracellular application of recombinant CDH23 and PCDH15 fragments, which included putative interaction domains (EC1). Both fragments inhibited development and regeneration of transduction but did not disrupt transduction in mature cells. PCDH15 fragments that carried a mutation in EC1 that causes deafness in humans did not inhibit transduction development or regeneration. Immunolocalization revealed wild-type fragments bound near the tips of hair cell stereocilia. Scanning electron micrographs revealed that hair bundles exposed to fragments had a reduced number of linkages aligned along the morphological axis of sensitivity of the bundle. Together, the data provide direct evidence implicating CDH23 and PCDH15 proteins in the formation of tip links during development and regeneration of mechanotransduction.
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cadherin 23 is a component of the tip link in hair cell stereocilia
Nature, 2004Co-Authors: Jan Siemens, Peter G. Gillespie, Concepcion Lillo, Rachel A Dumont, Anna Reynolds, David S Williams, Ulrich MüllerAbstract:Mechanoelectrical transduction, the conversion of mechanical force into electrochemical signals, underlies a range of sensory phenomena, including touch, hearing and balance. Hair cells of the vertebrate inner ear are specialized mechanosensors that transduce mechanical forces arising from sound waves and head movement to provide our senses of hearing and balance1,2; however, the mechanotransduction channel of hair cells and the molecules that regulate channel activity have remained elusive. One molecule that might participate in mechanoelectrical transduction is cadherin 23 (CDH23), as mutations in its gene cause deafness and age-related hearing loss3,4,5,6. Furthermore, CDH23 is large enough to be the tip link, the extracellular filament proposed to gate the mechanotransduction channel7. Here we show that antibodies against CDH23 label the tip link, and that CDH23 has biochemical properties similar to those of the tip link. Moreover, CDH23 forms a complex with myosin-1c, the only known component of the mechanotransduction apparatus8, suggesting that CDH23 and myosin-1c cooperate to regulate the activity of mechanically gated ion channels in hair cells.
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Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells
Nature, 2004Co-Authors: Christian Söllner, Ulrich Müller, Gerd-jörg Rauch, Jan Siemens, Robert Geisler, Stephan C. Schuster, Teresa NicolsonAbstract:Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels1. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing2. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction3,4. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (CDH23). Mutations in CDH23 also cause deafness and vestibular defects in mice and humans5,6,7,8,9, and the protein is present in hair bundles10,11. We show that zebrafish CDH23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputniktc317e larvae. Moreover, tip links are absent in larvae carrying weak alleles of CDH23 that affect mechanotransduction but not hair bundle integrity. We conclude that CDH23 is an essential tip link component required for hair-cell mechanotransduction.
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the usher syndrome proteins cadherin 23 and harmonin form a complex by means of pdz domain interactions
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Jan Siemens, Piotr Kazmierczak, Anna Reynolds, Melanie Sticker, Amanda Littlewoodevans, Ulrich MüllerAbstract:Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative adhesion receptors cadherin 23 (CDH23) and protocadherin 15 (PCDH15). We show here that CDH23 and harmonin form a protein complex. Two PDZ domains in harmonin interact with two complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because CDH23-deficient mice have splayed stereocilia, our data suggest that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle. Defects in the formation of this complex are predicted to disrupt stereocilia bundles and cause deafness in USH1 patients.