Role of myosin VI in the differentiation of cochlear hair cells

The mouse mutant Snell's waltzer (sv) has an intragenic deletion of the Myo 6 gene, which encodes the unconventional myosin molecule myosin VI (K. B. A vraham et al., 1995, Net. Genet. 11, 369-375). Snell's waltzer mutants exhi bit behavioural abnormalities suggestive of an inner ear defect, including lack of responsiveness to sound, hyperactivity, head tossing, and circling. We have investigated the effects of a lack of myosin VI on the development of the sensory hair cells of the cochlea in these mutants. In normal mice, the hair cells sprout microvilli on their upper surface, and some of these grow to form a crescent or V-shaped array of modified microvilli, the ster eocilia. In the mutants, early stages of stereocilia development appear to proceed normally because at birth many stereocilia bundles have a normal ap pearance, but in places there are signs of disorganisation of the bundles. Over the next few days, the stereocilia become progressively more disorgani sed and fuse together. Practically all hair cells show fused stereocilia by 3 days after birth, and there is extensive stereocilia fusion by 7 days. B y 20 days, giant stereocilia are observed on top of the hair cells. At 1 an d 3 days after birth, hair cells of mutants and controls take up the membra ne dye FM1-43, suggesting that endocytosis occurs in mutant hair cells. One possible model for the fusion is that myosin VI may be involved in anchori ng the apical hair cell membrane to the underlying actin-rich cuticular pla te, and in the absence of normal myosin VI this apical membrane will tend t o pull up between stereocilia, leading to fusion. (C) 1999 Academic Press.