Ca2+-activated Cl- channels (CaCCs) are ion channels that are opened by increases in cytosolic Ca2+ and selectively conduct Cl- and other anions down their electrochemical gradient. Their best known function is epithelial fluid secretion. CaCCs are encoded by members of two different gene families, Bestrophins and Anoctamins (also called TMEM16). Mutations in BEST1 cause a spectrum of retinal degenerations called bestrophinopthies. ANO1 and ANO2, while not yet linked directly to retinal disease, are expressed in a variety of cells in the retina including photoreceptors and RPE. Since their discovery in 2008, it has since become increasingly apparent that anoctamins are amazingly versatile: ANO1 has a very broad range of functions that encompass sensory transduction and adaptation, regulation of myoepithelial cell and smooth muscle tone, control of neuronal and cardiac excitability, and nociception. In addition, evidence is accumulating that ANO1 plays fundamental roles in cell biological processes like regulation of cell motility, proliferation, and primary ciliogenesis. Recently, we observed that ANO1, while spread over the cell surface in non-confluent cells, becomes concentrated in a distinctive apical torus (the nimbus) as cells become confluent and polarize. The nimbus becomes the site where the primary cilium emerges from the cell. The primary cilium, a non-motile cellular antenna that is packed with sensory receptors, plays a pivotal role in tissue morphogenesis and development and is closely linked to cell proliferation and migration. Mutations in various genes involved in ciliogenesis produce a diverse spectrum of human disorders called ciliopathies that are very frequently characterized by retinal degeneration. We have found that disrupting ANO1 function or expression has profound effects on the development of the primary cilium. The goal of this research is to elucidate the role of ANO1 in the genesis and function of the primary cilium. We hypothesize that ANO1 plays a key role in organizing a subdomain of the apical membrane to make it competent for ciliogenesis to occur. We imagine two mechanisms by which ANO1 may function in this context. (i) ANO1 may operate as a scaffold to organize and coordinate ciliogenic proteins at the apical membrane. This mechanism is supported by our proteomic data that ANO1 interacts with proteins essential for ciliogenesis and that these ciliary proteins regulate ANO1 currents. (ii) Alternatively, Cl- transport through ANO1 may play a role in ciliogenesis. This idea is supported by data that ANO1 channel blockers disrupt ciliogenesis and that the species of anion in the extracellular solution has profound effects on ciliogenesis. Because the primary cilium is a fundamental property of both photoreceptors and retinal pigment epithelial cells, understanding the role of ANO1 in primary ciliogenesis has important implications for retinal biology and therapy of retinal diseases.
Primary cilia are unique sensory appendages present on most cells of the body. Disruption of genes encoding ciliary proteins produce a range of disorders called ciliopathies that often include retinal degeneration. This application explores th workings of a Ca2+-activated Chloride Channel called ANO1 that is present in the primary cilium of retinal pigment epithelial cells and that we propose plays an important role in primary ciliogenesis and/or maintenance
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