The above enumeration does not conclusively summarize identities and functions of all hair-cell myosin isozymes. The RT-PCR screen described by Sole et al. (1994) demonstrated that other myosin isozymes, including myosin Iα and myosin X, are also found in hair-cell-containing epithelia; in addition, primer sets used may have missed other classes; for example, homologous of myosins III and Vb. Additional cataloging of myosins mRNAs from frog sacculus and other auditory and vestibular tissues will no doubt identify additional myosin isozymes expressed in hair cells. Myosin molecules besides myosin VI and VIIa are likely to be essential for hair cells. Genes for several myosin isozymes, including those for myosins Iβ, Iγ, and VIIb, are predicted to map closely to the chromosomal locations of at least one human deafness gene (Hasson et al. 1996). Mutations in their hair-cell myosin isozymes may not manifest as human deafnesses if the isozyme in question is employed for other essential roles. Although distribution of myosin molecules within the auditory and vestibular systems is complicated, we believe that a specific, principal role can be ascribed to each isozyme. Myosin V is not found in hair cells and likely serves the same role in afferent nerve processes that it plays elsewhere in the nervous system. Myosin Ī probably mediates adaptation and may contribute to transport of proteins throughout stereocilia. Myosin VI appears to cross-link actin filaments within the cuticular plate and perhaps between the cuticular plate and stereociliary rootlets; mutations in myosin VI may disrupt these structures and prevent bundle formation. Myosin VIIa may actually hold stereocilia together, mutations in myosin VIIa may therefore cause stereocilia to splay apart, preventing proper assembly into a hair bundle. Myosin Iβ, VI, and VIIa are each at unusually high concentrations in bundles of the most newly formed hair cells, usually at the sensory epithelium's periphery (Gillespie et al. 1993; T. Hasson et al., in prep.); these three isozymes may therefore play additional, more specialized roles during hair-bundle development (Tilney et al. 1992). In the future, we expect that exciting results will come from experiments designed to test these predictions. A key conclusion from hair- cell myosin localization is that these myosin molecules are not necessarily concentrated in regions of high actin density. Despite the similarity of their catalytic domains, each of the myosin isozymes found in hair cells has a distinctive subcellular localization. Furthermore, each hair-cell myosin isozyme appears in multiple specific locations. The ability of myosin molecules to bind to and translocate along actin filaments must therefore be heavily regulated; for dictating location, the affinity of myosin molecules for other proteins may be just as important as their affinity for actin. The nonhomologous tail domains of each class must contribute substantially to this differential localization. A critical goal for the field is therefore identification of hair-cell proteins that bind to myosin molecules, because their localization and abundance relative to each myosin isozyme may establish the final destination of a given myosin molecule. Finally, we wonder why myosin molecules would be employed in capacities that appear, at first consideration, to be entirely structural. In particular, our hypothesized roles for myosins VI and VIIa-maintaining cuticular-plate and bundle structural integrity-do not require force-producing molecules. Proteins that simply cross-link actin or connect actin to specific membrane receptors would seem to function adequately. Because the cell expends considerable energy to transcribe and translate relatively large myosin motor domains instead of smaller actin-binding structures, it seems likely that actin-activated ATPase plays a fundamental role in the behavior of these myosin isozymes. Because myosins VI and VIIa are not simply targeted to distal ends of actin filaments, but are instead found in association with specific actin-filament domains, the role of the motor activity must be relatively subtle. It seems likely that by understanding this paradox, we will understand the precise role of each myosin isozyme in the hair cell.
|Original language||English (US)|
|Number of pages||10|
|Journal||Cold Spring Harbor symposia on quantitative biology|
|State||Published - Dec 1 1996|
ASJC Scopus subject areas
- Molecular Biology