Abstract
An unconventional myosin encoded by the myosin VI gene (MYO6) contributes to hearing loss in humans. Homozygous mutations of MYO6 result in nonsyndromic profound congenital hearing loss, DFNB37. Kumamoto shaker/waltzer (ksv) mice harbor spontaneous mutations, and homozygous mutants exhibit congenital defects in balance and hearing caused by fusion of the stereocilia. We identified a Myo6c.1381G>A mutation that was found to be a p.E461K mutation leading to alternative splicing errors in Myo6 mRNA in ksv mutants. An analysis of the mRNA and protein expression in animals harboring this mutation suggested that most of the abnormal alternatively spliced isoforms of MYO6 are degraded in ksv mice. In the hair cells of ksv/ksv homozygotes, the MYO6 protein levels were significantly decreased in the cytoplasm, including in the cuticular plates. MYO6 and stereociliary taper-specific proteins were mislocalized along the entire length of the stereocilia of ksv/ksv mice, thus suggesting that MYO6 attached to taper-specific proteins at the stereociliary base. Histological analysis of the cochlear hair cells showed that the stereociliary fusion in the ksv/ksv mutants, developed through fusion between stereociliary bundles, raised cuticular plate membranes in the cochlear hair cells and resulted in incorporation of the bundles into the sheaths of the cuticular plates. Interestingly, the expression of the stereociliary rootlet-specific TRIO and F-actin binding protein (TRIOBP) was altered in ksv/ksv mice. The abnormal expression of TRIOBP suggested that the rootlets in the hair cells of ksv/ksv mice had excessive growth. Hence, these data indicated that decreased MYO6 levels in ksv/ksv mutants disrupt actin networks in the apical region of hair cells, thereby maintaining the normal structure of the cuticular plates and rootlets, and additionally provided a cellular basis for stereociliary fusion in Myo6 mutants.
Highlights
IntroductionThe inner ear hair cells are crucial to hearing and vestibular function
In vertebrates, the inner ear hair cells are crucial to hearing and vestibular function
We confirmed that the shaker/waltzer behavior of ksv/ksv mice was caused by stereociliary defects in vestibular hair cells, on the basis of comparison of Scanning electron microscopy (SEM) images between the +/+ and ksv/ksv mice (Fig 1C and 1D)
Summary
The inner ear hair cells are crucial to hearing and vestibular function. Several molecules that are functionally associated with the basal region of the stereocilia have been identified in genetic studies of deaf human patients as well as mouse models [6,7,8,9,10,11,12,13,14,15] Among these molecules, one unconventional myosin, myosin VI (MYO6), has been shown to play crucial roles in the constriction and integrity of the stereociliary base. The expression of MYO6 is concentrated in the basal region of the stereocilia, cuticular plate and cytoplasm [5, 6, 18,19,20,21]; MYO6 has been predicted to move toward the minus ends of the actin filaments located near the rootlets of the stereocilia [3, 21, 22]. Mutations in human MYO6 have been shown to cause recessive DFNB37 [24] and dominant DFNA22 [25] nonsyndromic hearing loss
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