The investigators' broad goal is to understand in molecular/cellular terms, the major features of outer segment assembly in photoreceptors and the role of the connecting cilium. The high turnover of the molecular components of photosensitive outer segments insures sustained function throughout life. It also presents a problem in that disruption of turnover can lead to diminution of function and to cell death. Factors adversely affecting photosensitive membrane turnover could be important in hereditary photoreceptor degeneration and/or age related macular degeneration. For example, some data suggests that the sensory cilium may be defective in forms of retinitis pigmentosa called Usher's syndrome. Since the assembly of outer segment occurs in association with the distal connecting cilium, and all components of outer segments are thought to pass from inner to outer segment via the cilium, knowledge of this process is important. Despite extraordinary advances in our knowledge of the photosensitive membrane system, there is an extreme paucity of data related to the molecular structure of the connecting cilium. The investigators have devised a strategy that takes advantage of the detergent stability of connecting cilium cross-linkers and their attached cell surface glycoconjugates. Beginning with the detergent extracted bovine ciliary axonemes and extending to in situ structure in intact cells the investigators plan to:
Specific Aim 1. To characterize multimolecular, glycoconjugate aggregates of high Mr on the connecting cilium. Emphasis will be on definition of polypeptide composition.
Specific Aim 2. To isolate and characterize large protein assemblages containing all or many of the proteins that make up the connecting cilium cross-linker. Emphasis is on the large cross-linking structures and their attachment to microtubules.
Specific Aim 3. To characterize kinesin-like proteins in photoreceptor ciliary axonemes with emphasis on their location and potential role as a transport motor.
| Lewis, Tylor R; Kundinger, Sean R; Link, Brian A et al. (2018) Kif17 phosphorylation regulates photoreceptor outer segment turnover. BMC Cell Biol 19:25 |
| Lewis, Tylor R; Zareba, Mariusz; Link, Brian A et al. (2018) Cone myoid elongation involves unidirectional microtubule movement mediated by dynein-1. Mol Biol Cell 29:180-190 |
| Lewis, Tylor R; Kundinger, Sean R; Pavlovich, Amira L et al. (2017) Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms. Dev Biol 425:176-190 |
| Collery, Ross F; Volberding, Peter J; Bostrom, Jonathan R et al. (2016) Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages. Invest Ophthalmol Vis Sci 57:6805-6814 |
| Besharse, Joseph C; McMahon, Douglas G (2016) The Retina and Other Light-sensitive Ocular Clocks. J Biol Rhythms 31:223-43 |
| Miesfeld, Joel B; Gestri, Gaia; Clark, Brian S et al. (2015) Yap and Taz regulate retinal pigment epithelial cell fate. Development 142:3021-32 |
| Fogerty, Joseph; Besharse, Joseph C (2014) Subretinal infiltration of monocyte derived cells and complement misregulation in mice with AMD-like pathology. Adv Exp Med Biol 801:355-63 |
| Bader, Jason R; Kusik, Brandon W; Besharse, Joseph C (2012) Analysis of KIF17 distal tip trafficking in zebrafish cone photoreceptors. Vision Res 75:37-43 |
| Wong-Riley, Margaret T T; Besharse, Joseph C (2012) The kinesin superfamily protein KIF17: one protein with many functions. Biomol Concepts 3:267-282 |
| Malicki, Jarema; Besharse, Joseph C (2012) Kinesin-2 family motors in the unusual photoreceptor cilium. Vision Res 75:33-6 |
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