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Auditory hair cell defects as potential cause for sensorineural deafness in Wolf-Hirschhorn syndrome.

Ahmed M, Ura K, Streit A - Dis Model Mech (2015)

Bottom Line: Although auditory hair cells are specified normally, their stereocilia hair bundles required for sound perception fail to develop the appropriate morphology.Furthermore, the orientation and cellular organisation of cochlear hair cells and their innervation are defective.These findings identify, for the first time, the likely cause of sensorineural hearing loss in individuals with WHS.

View Article: PubMed Central - PubMed

Affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, SE1 9RT, UK.

No MeSH data available.


Related in: MedlinePlus

Stereocilia formation is perturbed in WHSC1−/− hair cells. (A-I) Basal region of E18.5 wild-type and mutant organ of Corti labelled with acetylated α-tubulin to visualise kinocilia (red) and phalloidin to reveal stereocilia (green). Kinocilia and stereocilia formation is abnormal in the mutant cochlea. (J) Quantification and schematic representation of the hair bundle defects in wild-type (n=10), heterozygous (n=10) and homozygous (n=10) animals. In mutants, the kinocilia (black dots) and stereocilia (purple) are either absent or have largely abnormal orientation. Those that do have a kinocilia can either have no stereociliary hair bundles or these bundles are localised around the cell perimeter. Scale bars: 10 μm. Asterisk: (D) central position of kinocilia rather than peripheral; (G) no kinocilium. Arrowheads, outer hair cell kinocilia; arrows, inner hair cell kinocilia.
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DMM019547F7: Stereocilia formation is perturbed in WHSC1−/− hair cells. (A-I) Basal region of E18.5 wild-type and mutant organ of Corti labelled with acetylated α-tubulin to visualise kinocilia (red) and phalloidin to reveal stereocilia (green). Kinocilia and stereocilia formation is abnormal in the mutant cochlea. (J) Quantification and schematic representation of the hair bundle defects in wild-type (n=10), heterozygous (n=10) and homozygous (n=10) animals. In mutants, the kinocilia (black dots) and stereocilia (purple) are either absent or have largely abnormal orientation. Those that do have a kinocilia can either have no stereociliary hair bundles or these bundles are localised around the cell perimeter. Scale bars: 10 μm. Asterisk: (D) central position of kinocilia rather than peripheral; (G) no kinocilium. Arrowheads, outer hair cell kinocilia; arrows, inner hair cell kinocilia.

Mentions: Hair cell stereocilia are crucial for the function of these cells as mechanosensory cells and to transmit sound information to the auditory nuclei in the brain stem (Yoshida and Liberman, 1999). Stereocilia develop on the apical surface of each hair cell and they can be visualised by Phalloidin to label F-actin polymers. Before morphogenesis of the hair bundle stereocilia, a specialised primary cilium, the kinocilium, visualised by acetylated α-tubulin, forms at the apical surface of each hair cell. As the kinocilium moves towards the cell periphery, actin stereocilia begin to form around it into a distinct morphology (inverted ‘V’ in OHCs and ‘C’ in IHCs). This arrangement of the hair bundle stereocilia is a manifestation of planar cell polarity (PCP; Ezan and Montcouquiol, 2013; Goodrich and Strutt, 2011; Sienknecht et al., 2014). At E18.5, hair cells in the base of the cochlea already show appropriate stereocilia morphology in control animals: they are aligned and orientated in the same direction (Fig. 7A-C; supplementary material Fig. S3A). Although kinocilia and stereocilia are present in WHSC1+/− and WHSC1−/− mutants, they exhibit abnormal shape, length and orientation (Fig. 7D-J; supplementary material Fig. S3G,M). Frequently, stereociliary hair bundles were localised around the cell periphery. In homozygous WHSC1−/− mice, a substantial proportion of OHCs and IHCs lacked kinocilia or stereocilia (Fig. 7D-J; supplementary material Fig. S3G,M; asterisk). Taken together, our data suggest that WHSC1 is required during hair cell differentiation as the cells begin to organise themselves into distinct rows and form stereocilia, orientated in one direction.Fig. 7.


Auditory hair cell defects as potential cause for sensorineural deafness in Wolf-Hirschhorn syndrome.

Ahmed M, Ura K, Streit A - Dis Model Mech (2015)

Stereocilia formation is perturbed in WHSC1−/− hair cells. (A-I) Basal region of E18.5 wild-type and mutant organ of Corti labelled with acetylated α-tubulin to visualise kinocilia (red) and phalloidin to reveal stereocilia (green). Kinocilia and stereocilia formation is abnormal in the mutant cochlea. (J) Quantification and schematic representation of the hair bundle defects in wild-type (n=10), heterozygous (n=10) and homozygous (n=10) animals. In mutants, the kinocilia (black dots) and stereocilia (purple) are either absent or have largely abnormal orientation. Those that do have a kinocilia can either have no stereociliary hair bundles or these bundles are localised around the cell perimeter. Scale bars: 10 μm. Asterisk: (D) central position of kinocilia rather than peripheral; (G) no kinocilium. Arrowheads, outer hair cell kinocilia; arrows, inner hair cell kinocilia.
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Related In: Results  -  Collection

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DMM019547F7: Stereocilia formation is perturbed in WHSC1−/− hair cells. (A-I) Basal region of E18.5 wild-type and mutant organ of Corti labelled with acetylated α-tubulin to visualise kinocilia (red) and phalloidin to reveal stereocilia (green). Kinocilia and stereocilia formation is abnormal in the mutant cochlea. (J) Quantification and schematic representation of the hair bundle defects in wild-type (n=10), heterozygous (n=10) and homozygous (n=10) animals. In mutants, the kinocilia (black dots) and stereocilia (purple) are either absent or have largely abnormal orientation. Those that do have a kinocilia can either have no stereociliary hair bundles or these bundles are localised around the cell perimeter. Scale bars: 10 μm. Asterisk: (D) central position of kinocilia rather than peripheral; (G) no kinocilium. Arrowheads, outer hair cell kinocilia; arrows, inner hair cell kinocilia.
Mentions: Hair cell stereocilia are crucial for the function of these cells as mechanosensory cells and to transmit sound information to the auditory nuclei in the brain stem (Yoshida and Liberman, 1999). Stereocilia develop on the apical surface of each hair cell and they can be visualised by Phalloidin to label F-actin polymers. Before morphogenesis of the hair bundle stereocilia, a specialised primary cilium, the kinocilium, visualised by acetylated α-tubulin, forms at the apical surface of each hair cell. As the kinocilium moves towards the cell periphery, actin stereocilia begin to form around it into a distinct morphology (inverted ‘V’ in OHCs and ‘C’ in IHCs). This arrangement of the hair bundle stereocilia is a manifestation of planar cell polarity (PCP; Ezan and Montcouquiol, 2013; Goodrich and Strutt, 2011; Sienknecht et al., 2014). At E18.5, hair cells in the base of the cochlea already show appropriate stereocilia morphology in control animals: they are aligned and orientated in the same direction (Fig. 7A-C; supplementary material Fig. S3A). Although kinocilia and stereocilia are present in WHSC1+/− and WHSC1−/− mutants, they exhibit abnormal shape, length and orientation (Fig. 7D-J; supplementary material Fig. S3G,M). Frequently, stereociliary hair bundles were localised around the cell periphery. In homozygous WHSC1−/− mice, a substantial proportion of OHCs and IHCs lacked kinocilia or stereocilia (Fig. 7D-J; supplementary material Fig. S3G,M; asterisk). Taken together, our data suggest that WHSC1 is required during hair cell differentiation as the cells begin to organise themselves into distinct rows and form stereocilia, orientated in one direction.Fig. 7.

Bottom Line: Although auditory hair cells are specified normally, their stereocilia hair bundles required for sound perception fail to develop the appropriate morphology.Furthermore, the orientation and cellular organisation of cochlear hair cells and their innervation are defective.These findings identify, for the first time, the likely cause of sensorineural hearing loss in individuals with WHS.

View Article: PubMed Central - PubMed

Affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, SE1 9RT, UK.

No MeSH data available.


Related in: MedlinePlus