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Myosin VIIA Regulates Microvillus Morphogenesis and Interacts With ß 2014. Published by The Company of Biologists Ltd | Journal of Cell Science (2014) 127, 4821–4832 doi:10.1242/jcs.099242 RESEARCH ARTICLE Myosin VIIA regulates microvillus morphogenesis and interacts with cadherin Cad99C in Drosophila oogenesis Cory Glowinski*, Ri-Hua Sandy Liu*, Xi Chen, Audrey Darabie and Dorothea Godt` ABSTRACT cytocortex (reviewed by Frolenkov et al., 2004). The dynamics of actin polymerization and depolymerization control the length Microvilli and related actin-based protrusions permit multiple of microvilli. A number of factors have been identified that interactions between cells and their environment. How the shape, contribute to the length regulation of microvilli or microvillus- length and arrangement of microvilli are determined remains largely derived stereocilia and their organization and arrangement on the unclear. To address this issue and explore the cooperation of the apical surface of epithelial cells. Many of these factors directly two main components of a microvillus, the central F-actin bundle bind to actin in protrusions, either cross-linking actin filaments or and the enveloping plasma membrane, we investigated the linking them to the plasma membrane (reviewed by Lin et al., expression and function of Myosin VIIA (Myo7A), which is 2005; Sekerkova´ et al., 2006; Manor and Kachar, 2008; Tepass, encoded by crinkled (ck), and its interaction with cadherin 2009; Fehon et al., 2010). In particular, myosin motor proteins, Cad99C in the microvilli of the Drosophila follicular epithelium. which bind to and travel along actin filaments, control multiple Myo7A is present in the microvilli and terminal web of follicle cells, processes in microvilli and stereocilia. Myosins have been and associates with several other F-actin-rich structures in the implicated in transporting, anchoring and concentrating protein ovary. Loss of Myo7A caused brush border defects and a reduction complexes and membrane vesicles, in exerting tension force on in the amount of the microvillus regulator Cad99C. We show that the plasma membrane and in influencing the structure of actin Myo7A and Cad99C form a molecular complex and that the networks (reviewed by Krendel and Mooseker, 2005; Nambiar cytoplasmic tail of Cad99C recruits Myo7A to microvilli. Our data et al., 2010; Schwander et al., 2010; Hartman et al., 2011). indicate that Myo7A regulates the structure and spacing of microvilli, One of the myosins that regulates actin-rich membrane and interacts with Cad99C in vivo. A comparison of the mutant protrusions in Drosophila and vertebrates is Myosin VIIA phenotypes suggests that Myo7A and Cad99C have co-dependent (Myo7A) (reviewed by El-Amraoui et al., 2008). This molecule is highly conserved in structure and sequence between flies and and independent functions in microvilli. mammals. Myo7A consists of a motor head domain, a neck with KEY WORDS: Myosin VIIA, crinkled, Cad99C, Microvillus brush IQ (isoleucine-glutamine) motifs and a tail containing MyTH4 border, Drosophila oogenesis (myosin tail homology) and FERM (Four-point-one, Ezrin, Radixin, Moesin)-MyTh7 domains and an SH3 (src homology F3) sequence (Kiehart et al., 2004). The head domain provides INTRODUCTION ATPase-dependent plus-end-directed motor activity along actin Actin-filament-based protrusions of the plasma membrane have filaments (Udovichenko et al., 2002; Inoue and Ikebe, 2003). The important functions in cell structure, behavior, cell–cell or cell– activity of Myo7A seems to be controlled by the density of the environment interactions and physiology. Finger-like protrusions actin network, as binding to actin is required for both the release called microvilli are often found on the apical surface of of the autoinhibitory interaction between the head motor domain epithelial cells. The microvilli of the ovarian follicular and the second FERM-MyTH7 domain and the subsequent epithelium in Drosophila are a prominent example (Mahowald activation of the ATPase (Yang et al., 2009; Umeki et al., 2009; and Kambysellis, 1980; Trougakos et al., 2001; D’Alterio et al., Inoue and Ikebe, 2003). Once activated, Myo7A appears to be 2005; Schlichting et al., 2006). Furthermore, microvilli can predominantly locked in an ADP-bound state, in which it strongly give rise to complex structures in sensory organs, such as binds to actin. Its high duty ratio allows Myo7A to act as a rhabdomeres and bristles in insects and hair cell stereocilia in processive motor when dimerized (Watanabe et al., 2006; Yang the vertebrate ear, which transduce light and mechanosensory et al., 2006; Haithcock et al., 2011). Myo7A is thought to stimuli, respectively (reviewed by DeRosier and Tilney, 2000; dimerize with the help of factors binding to its tail region (Yang Frolenkov et al., 2004). et al., 2009; Umeki et al., 2009; Haithcock et al., 2011). The high- A microvillus contains a bundle of parallel actin filaments duty processive motor activity of Myo7A is consistent with a enveloped by plasma membrane. Plus ends of actin filaments function in transporting cargo or in anchoring plasma membrane point distally and minus ends are anchored in the terminal web, a components to the actin bundle to generate tension forces meshwork of actin filaments and associated proteins in the apical (reviewed by El-Amraoui et al., 2008). Mutations in the gene crinkled (ck), which encodes Drosophila Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Myo7A, cause pronounced structural defects in apical actin-based Toronto, ON, M5S 2M6, Canada. protrusions of the epidermis, such as mechanosensory bristles and *These authors contributed equally to this work non-innervated denticles and hairs (trichomes) (Nu¨sslein-Volhard `Author for correspondence ([email protected]) et al., 1984; Gubb et al., 1984; Turner and Adler, 1998; Kiehart et al., 2004). Myo7A collaborates with the membrane-bound Received 19 August 2011; Accepted 1 September 2014 extracellular protein Miniature and the actin cross-linking factor Journal of Cell Science 4821 RESEARCH ARTICLE Journal of Cell Science (2014) 127, 4821–4832 doi:10.1242/jcs.099242 Forked in denticle formation (Bejsovec and Chao, 2012). germline and associated somatic cells throughout oogenesis, Moreover, Myo7A-deficient flies are deaf, owing to defects in showing developmentally regulated changes in expression level the extracellular dendritic caps that attach the auditory sensory and subcellular distribution (Fig. 1). The main characteristics of cells to the epidermis (Todi et al., 2005; Todi et al., 2008). the subcellular localization of Myo7A are a punctate distribution In vertebrates, Myo7A belongs to a group of molecules that are throughout the cytoplasm and association with specific F-actin- linked to Usher type I syndrome (USH1; reviewed by El-Amraoui rich cell structures. et al., 2008). A hallmark trait of Myo7A mutants in vertebrates is In the germline, the amount of Myo7A protein increased during deafness, which is caused, at least in part, by defects in the follicle formation in the germarium and again at mid-oogenesis stereocilia of hair cells, including an abnormal arrangement of (stage 9) and was prominent until late oogenesis (Fig. 1A–J). stereocilia, loss of cohesion between stereocilia, defects in length Myo7A accumulated in the F-actin-rich cytocortex of the oocyte regulation of stereocilia and disruption of links between stereocilia (stage 3 onwards, peaking at stages 9–10a) and, to a lesser degree, (Self et al., 1998; Ernest et al., 2000; Ku¨ssel-Andermann et al., 2000; in the cortex of nurse cells (stage 6 onwards) (Fig. 1B–E). Michalski et al., 2007; Prosser et al., 2008; Lefe`vre et al., 2008; Myo7A was highly concentrated at two prominent F-actin Rzadzinska et al., 2009). Myo7A has been found to interact with structures. It colocalized with nurse cell struts (Fig. 1G,I; several transmembrane proteins and scaffold proteins, promoting Fig. 2A), which consist of a series of overlapping bundles of their presence and possibly transport in stereocilia (reviewed by El- parallel-oriented unidirectional actin filaments that anchor the Amraoui et al., 2008). Particularly well documented is the nurse cell nuclei (Tilney et al., 1996). Myo7A was also found at association of Myo7A with other USH1-linked proteins, cadherin ring canals (Fig. 1C; Fig. 2B), cytoplasmic bridges that connect 23 (CDH23), PDZ domain protein harmonin, scaffold protein SANS the cells of a germline cyst. Ring canals consist of a dense inner and the Ca2+ and integrin-binding protein CIB2 (Boe¨da et al., 2002; ring of bipolar actin filaments and an associated crown and Adato et al., 2005; Bahloul et al., 2010; Grati and Kachar, 2011; fishing-weir-like basket of needle-like actin bundles (Nicolas Sahly et al., 2012; Riazuddin et al., 2012). Data corroborate the et al., 2009; reviewed by Hudson and Cooley, 2002). Myo7A was model that Myo7A forms a tension-generating link between the F- strongly enriched at the crown (Fig. 2B) and basket (not shown), actin core of a stereocilium and CDH23 in the plasma membrane but little was seen at the inner ring (Fig. 2B). that is crucial for the function of the tip link, a connection between Myo7A was also expressed by somatic cells of the ovary, stereocilia that is thought to be involved in the mechanotransduction including all follicle cells (Fig. 1A–L). Compared with the of hair cells (Grati and Kachar, 2011; Bahloul et al., 2010). germline, somatic expression was relatively low in early stages Furthermore, in vitro data indicate
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