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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

Development of cochlear and vestibular hair cells. (A,B) E16.5 wild-type and mutant cochlea revealing ATOH1 expression. (C,D) Immunolabelling of mutant cochlea and vestibule for MYO7A (green) counterstained with Hoechst to label nuclei (blue). Auditory and vestibular hair cell development is normal in WHSC1−/− mice. (E) E18.5 cochleae stained with Hoechst. Scale bars: 200 μm (A-D); 500 μm (E). l, lateral crista; a, anterior crista; u, utricle; s, saccule.
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DMM019547F2: Development of cochlear and vestibular hair cells. (A,B) E16.5 wild-type and mutant cochlea revealing ATOH1 expression. (C,D) Immunolabelling of mutant cochlea and vestibule for MYO7A (green) counterstained with Hoechst to label nuclei (blue). Auditory and vestibular hair cell development is normal in WHSC1−/− mice. (E) E18.5 cochleae stained with Hoechst. Scale bars: 200 μm (A-D); 500 μm (E). l, lateral crista; a, anterior crista; u, utricle; s, saccule.

Mentions: Although WHSC1 mutant inner ears are smaller, their gross morphology is normal. We next sought to determine whether the cellular anatomy of the cochlear and vestibular structures is affected in WHSC1 mutants. The transcription factor ATOH1 is expressed in cells committed to the hair cell lineage and functions upstream of the differentiation marker MYO7A (Bermingham et al., 1999; Chen and Segil, 1999). ATOH1 is expressed normally in vestibular (not shown) and in auditory hair cells in both WHSC1−/− and WHSC1+/− inner ears (Fig. 2A,B; not shown). The size of the cochlea was slightly, but not significantly, shorter in heterozygous animals (3264±41 μm vs 3276±65 μm; n=3, P=0.8), but significantly decreased by 22% (2541±113 μm vs 3276±65 μm; n=3, P=0.002) in homozygous mutants (Fig. 2E), consistent with a global reduction in the size of the WHSC1−/− mutants. However, the number of cochlear turns was unaffected (Fig. 2A,B) and the expression of MYO7A was initiated normally (Fig. 2C,D), suggesting that WHSC1 is not required for cochlear duct elongation or the formation and differentiation of hair cells.Fig. 2.


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

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

Development of cochlear and vestibular hair cells. (A,B) E16.5 wild-type and mutant cochlea revealing ATOH1 expression. (C,D) Immunolabelling of mutant cochlea and vestibule for MYO7A (green) counterstained with Hoechst to label nuclei (blue). Auditory and vestibular hair cell development is normal in WHSC1−/− mice. (E) E18.5 cochleae stained with Hoechst. Scale bars: 200 μm (A-D); 500 μm (E). l, lateral crista; a, anterior crista; u, utricle; s, saccule.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4582100&req=5

DMM019547F2: Development of cochlear and vestibular hair cells. (A,B) E16.5 wild-type and mutant cochlea revealing ATOH1 expression. (C,D) Immunolabelling of mutant cochlea and vestibule for MYO7A (green) counterstained with Hoechst to label nuclei (blue). Auditory and vestibular hair cell development is normal in WHSC1−/− mice. (E) E18.5 cochleae stained with Hoechst. Scale bars: 200 μm (A-D); 500 μm (E). l, lateral crista; a, anterior crista; u, utricle; s, saccule.
Mentions: Although WHSC1 mutant inner ears are smaller, their gross morphology is normal. We next sought to determine whether the cellular anatomy of the cochlear and vestibular structures is affected in WHSC1 mutants. The transcription factor ATOH1 is expressed in cells committed to the hair cell lineage and functions upstream of the differentiation marker MYO7A (Bermingham et al., 1999; Chen and Segil, 1999). ATOH1 is expressed normally in vestibular (not shown) and in auditory hair cells in both WHSC1−/− and WHSC1+/− inner ears (Fig. 2A,B; not shown). The size of the cochlea was slightly, but not significantly, shorter in heterozygous animals (3264±41 μm vs 3276±65 μm; n=3, P=0.8), but significantly decreased by 22% (2541±113 μm vs 3276±65 μm; n=3, P=0.002) in homozygous mutants (Fig. 2E), consistent with a global reduction in the size of the WHSC1−/− mutants. However, the number of cochlear turns was unaffected (Fig. 2A,B) and the expression of MYO7A was initiated normally (Fig. 2C,D), suggesting that WHSC1 is not required for cochlear duct elongation or the formation and differentiation of hair cells.Fig. 2.

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