View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Dispatch R315 Cell adhesion: Ushering in a new understanding of myosin VII Markus Maniak The myosin VII motor protein has recently been found namely along the length of stereocilia beside the lateral to have a role in cell adhesion. This new function is linkers that tie stereocilia together, and in the pericuticu- conserved from amoebae to man and provides an lar necklace — a band of apical cytoplasm surrounding the explanation for deafness in Usher syndrome patients. cuticular plate that is densely populated with vesicles. Address: Abteilung Zellbiologie, Universität GhK, Heinrich-Plett-Str. 40, D-34109 Kassel, Germany. Myosin VIIa must be specifically important for hair cell E-mail: [email protected] function, because patients carrying mutations in the corre- sponding gene suffer from deafness [4]. This disease is Current Biology 2001, 11:R315–R317 called Usher syndrome type 1B and also affects retinal 0960-9822/01/$ – see front matter integrity [5]. Mutant model systems that replicate the © 2001 Elsevier Science Ltd. All rights reserved. auditory symptoms and balancing defects of Usher disease are the shaker-1 mouse [6] and the mariner zebrafish [7]: Myosins are largely seen as molecular motors that trans- hair cells are used in the zebrafish for detection of water port cargo along cables of actin filaments. These motor movements in the lateral line organ. Cells and tissue proteins consist of a head domain bearing the motor activ- obtained from these model organisms allow us to study ity and a variable tail region. Variations in the head domain the functional consequences of defective myosin VIIa. affect the velocity of the motor, whereas the sequence of the tail domain provides the specificity for cargo binding. Firstly, the localisation of myosin VIIa to the vesicle-rich In the simplest case, one myosin binds via its tail to zone of the pericuticular necklace prompted experiments another myosin to assemble the bipolar thick filament that on vesicular traffic [8]. Indeed, endocytosis of a mem- powers muscle contraction. In non-muscle cells an ever- brane-labelling styryl dye is greatly perturbed in the hair increasing set of different, so-called unconventional, myosin cells from mariner fish. Interestingly, the pharmacological molecules is expressed [1]. Apart from a few exceptions, properties and the fast time-course of this endocytic process the intracellular cargo of these myosins and therefore the are suggestive of the type of rapid endocytosis that oper- roles of these myosins in the cell remain unknown. A twist ates at synapses to ensure membrane recycling after exo- to the classical view of myosin function comes from a cytosis of neurotransmitters [9]. It is therefore possible study in a recent issue of Current Biology on the unicellular that future studies may uncover a function for myosin VII eukaryote Dictyostelium that has revealed a role for the in synaptic transmission — yet another case to be solved unconventional myosin VII in cell adhesion [2]. This in a suitable model system. result is surprisingly congruent with the proposed role for myosin VIIa in auditory perception in vertebrates. Secondly, the localisation of myosin VIIa to stereocilia indeed appears to have a role in maintaining the organisa- A cell type in which structural organisation beautifully tion of the apical brush. The conical bundle of stereocilia reflects physiological function is the hair cell of the inner present on hair cells of wild-type fish appears rather ear (Figure 1a). It is largely columnar in shape and, from splayed in the mariner mutants, indicating that myosin VIIa its apical side, a staggered arrangement of finger-like pro- contributes to the adhesion between adjacent stereocilia trusions, the stereocilia, project into the fluid-filled cavity [7]. The same is true for the shaker-1 mouse mutants [6]. of the inner ear. Upon arrival of a sound wave, the stere- To further analyse how myosin VIIa is linked to stereocilia ocilia are deflected and the mechanical stimulus is con- adhesion, Christine Petit and colleagues [10] launched a verted into an electric signal. This mechanical sensor is yeast two-hybrid screen to identify proteins interacting mainly constructed from actin filaments. Bundles of F- with the myosin VIIa tail. This screen turned up vezatin, a actin build the core of stereocilia from tip to bottom. Their novel transmembrane protein that localises to the lateral rootlets are immersed in a dense actin cushion underlying links connecting stereocilia as well as to cell–cell adherens the apical pole of the cell, called the cuticular plate. junctions with neighbouring cells. Diverse myosins appear in various locations within the These authors went on to show that vezatin’s association hair cell [3]. Stereocilia tips contain myosin Ib which may with adherens junctions is dependent on the cad- be tied to a molecular spring connecting the tips. The cutic- herin–catenin complex, which mediates Ca2+-dependent ular plate is rich in myosin VI which anchors the rootlets cell–cell adhesion. Together these results suggest a sur- of the stereocilia in the cell and may form their basal con- prising new link between myosin VIIa and cell adhesion striction. Myosin VIIa pops up in two interesting locations, [10]. Overwhelming support for this newly established R316 Current Biology Vol 11 No 8 Figure 1 (a) Hair cell (b) Dictyostelium Tip link F-actin Particle I Myosin I Stereocilia VI Myosin VI VII Myosin VII C Catenin Vezatin Cadherin Lateral links Current Biology Spatial versus temporal separation of myosin activity in a hair cell and clockwise and protein localisation is taken from various studies Dictyostelium. (a) Apical part of a hair cell. Left: apical endocytosis is [2,24,25]. Myosin VII first localises to the tip of a filopod that contacts dependent on myosin VII. Middle: two stereocilia connected by a tip a particle (top). After the particle adheres to the surface (upper right) link with associated myosin I (for a possible function, see [23]). Lateral the membrane develops into a cup-like structure lined with myosin VII connections between stereocilia involve vezatin and myosin VII and (lower right). When the phagocytic cup covers more than half of the possibly cadherin and catenin. Bundles of actin run down the particle, myosin VII dissociates from the membrane (bottom) and stereocilia and terminate in the cuticular plate, where they are phagocytosis is completed in the absence of myosin VII. Myosin I, a anchored by myosin VI. Right: cell–cell adherens junction composed of known component of phagocytic cups, is assumed to associate with vezatin and myosin VII and possibly cadherin and catenin, linked to an the membrane of the incipient phagocytic cup (upper right), but not F-actin belt. (b) Dictyostelium undergoes rapid shape changes during dissociate from the phagosome until it has been completely engulfed phagocytosis. Different stages of particle uptake are arranged (upper left). connection comes from the recent identification of new [16]. Further dissection of this defect now reveals that the cadherins that are defective in patients suffering from adhesion of particles to the cell surface is the step depen- Usher syndrome 1D [11] and in the corresponding mouse dent on myosin VII [2]. mutants [12,13]. Hair cells from affected mice show disor- ganised stereocilia and splayed sensory cones, highly remi- These authors go on to show that cell migration is also not niscent of the phenotype observed in myosin VIIa typical, in that the leading edge of the cell frequently mutants. This loss of structural integrity is the obvious detaches from the substratum and a phase of chaotic move- cause of hereditary deafness. ments off the surface ensues. Finally, myosin VII mutants are also impaired in Ca2+-dependent cell–cell adhesion, How general is this newly discovered link between which is probably mediated by a Dictyostelium cadherin myosin VII and cell adhesion? The undisputed lower end equivalent [17]. This list of defects, all related to cell on the scale of model organisms is the soil amoeba Dic- adhesion, is strikingly similar to the phenotypes observed tyostelium (Figure 1b). Nowadays it has a good reputation in a Dictyostelium mutant lacking talin, a protein thought to for studies on cell adhesion and even more so for work on link the actin cytoskeleton to adhesive cell-surface recep- the dynamics of the cytoskeleton. Cell adhesion proteins tors [18]. Yet another common feature of both talin and have been characterised down to the amount of force myosin VII is the specificity of their localisation to the tips developed between a single pair of molecules [14], and of filopods emanating from the amoebal surface [2,19]. the myosin repertoire comprising a dozen members [15] currently outnumbers that in hair cells. In a recent issue Now that the role of class VII myosins in the formation of of Current Biology, Margaret Titus and colleagues [2] cell–cell and cell–substrate contacts appears to be firmly analyse a Dictyostelium cell line that lacks myosin VII using established in biology and conserved in evolution, the sophisticated assays which are equally sensitive and sensi- question of its molecular mechanism remains to be dis- ble. Myosin VII mutants are impaired in phagocytosis cussed. First, it is important to note that myosin VII really Dispatch R317 is a molecular motor — that is, it is capable of moving on 6. Self T, Mahony M, Fleming J, Walsh J, Brown SD, Steel KP: Shaker-1 mutations reveal roles for myosin VIIA in both development and actin filaments at a decent speed [20]. One model for its function of cochlear hair cells. Development 1998, 125:557-566. function suggests that myosin VII grabs membrane pro- 7.