The long-term goal of our laboratories is to elucidate the mechanisms that control hair cell development and function, and ascertain the defects in this process that cause deafness. We propose here to identify and study proteins that physically and functionally interact with MYO7A and therefore mediate its function in hair cells. Based on published and preliminary data, we hypothesize that MYO7A has a three-fold function in hair cells, regulating the transport of proteins critical for hair bundle adhesion and actin polymerization and directly controlling mechanotransduction. To test our hypothesis, we will: (i) define the protein complexes that mediate stereocilia adhesion, focusing on those consisting of PCDH15 and GRP98; (ii) determine how MYO7A complexes regulate stereocilia length, focusing initially on the complex with CAPZ that we have defined; (iii) specify how MYO7A and its interacting proteins control mechanotransduction. Our preliminary data show the feasibility of our approach. We have already identified hair bundle proteins that interact with MYO7A and mediate its function. We anticipate that some of the novel interaction partners of MYO7A will be affected in genetic diseases that cause hearing impairment.
Public Health Relevance Hearing loss is a major health problem that significantly affects the life quality of affected individuals. Many forms of hearing loss are genetic in origin and affect hair cells, the mechanosensors that convert sound induced vibrations into electrical signals. We propose here to identify components of the machinery that regulates hair cell development and function, and how mutations in the genes that encode these components lead to hearing loss.
| Liu, Chang; Luo, Na; Tung, Chun-Yu et al. (2018) GRXCR2 Regulates Taperin Localization Critical for Stereocilia Morphology and Hearing. Cell Rep 25:1268-1280.e4 |
| Wu, Zizhen; Grillet, Nicolas; Zhao, Bo et al. (2017) Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci 20:24-33 |
| Avenarius, Matthew R; Krey, Jocelyn F; Dumont, Rachel A et al. (2017) Heterodimeric capping protein is required for stereocilia length and width regulation. J Cell Biol 216:3861-3881 |
| Morgan, Clive P; Krey, Jocelyn F; Grati, M'hamed et al. (2016) PDZD7-MYO7A complex identified in enriched stereocilia membranes. Elife 5: |
| Zhao, Bo; Müller, Ulrich (2015) The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 34:172-9 |
