The means by which cells regulate the size of their organelles is a fundamental unanswered question in cell biology. Cilia and flagella provide a convenient model system to study the general question of organelle size control due to their simple one- dimensional shape. Assembly of cilia and flagella requires a kinesin based motility called intraflagellar transport (IFT), and this transport is also required to maintain ciliary length afte assembly. The central role of IFT in ciliary assembly, combined with the fact that perturbations in IFT can lead to cilia-related diseases, has focused attention on the mechanisms that regulate IFT activity. We have used quantitative live cell image analysis to show that IFT particles are injected into the flagellum at a rate that depends on the flagellar length, suggesting some regulatory linkage between flagellar length and IFT injection, but the mechanism of this regulation is not understood. This proposal will test specific models for how length may regulate IFT using a combination of quantitative live cell image analysis and experimental perturbations, coupled with modeling and nonlinear time series analysis methods. We will also integrate IFT regulation with regulation of disassembly and of precursor synthesis into a combined control system model based on three separate feedback loops, and use experimental perturbations to test the contributions that individual feedback loops make to overall system performance. Our work combines quantitative live cell imaging and computational modeling with the powerful genetics of the unicellular model organism Chlamydomonas for probing flagellar dynamics.
Cilia are motile structures that drive fluid flows and sense chemical signals. Patients with defects in cilia suffer from a range of debilitating symptoms including hydrocephalus and polycystic kidney disease, in some cases as a result of abnormally short or long cilia. Our study will reveal how genes could alter the length of these structures to ensure normal function.
| Bhaduri, Sayantan; Ranjan, Nihar; Arya, Dev P (2018) An overview of recent advances in duplex DNA recognition by small molecules. Beilstein J Org Chem 14:1051-1086 |
| Hendel, Nathan L; Thomson, Matthew; Marshall, Wallace F (2018) Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport. Biophys J 114:663-674 |
| Chang, Amy Y; Marshall, Wallace F (2017) Organelles - understanding noise and heterogeneity in cell biology at an intermediate scale. J Cell Sci 130:819-826 |
| Ishikawa, Hiroaki; Marshall, Wallace F (2017) Testing the time-of-flight model for flagellar length sensing. Mol Biol Cell 28:3447-3456 |
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| Kamiyama, Daichi; Sekine, Sayaka; Barsi-Rhyne, Benjamin et al. (2016) Versatile protein tagging in cells with split fluorescent protein. Nat Commun 7:11046 |
| Ludington, William B; Ishikawa, Hiroaki; Serebrenik, Yevgeniy V et al. (2015) A systematic comparison of mathematical models for inherent measurement of ciliary length: how a cell can measure length and volume. Biophys J 108:1361-1379 |
| Marshall, Wallace F (2015) Subcellular size. Cold Spring Harb Perspect Biol 7: |
| Marshall, Wallace F (2015) How Cells Measure Length on Subcellular Scales. Trends Cell Biol 25:760-768 |
| Ishikawa, Hiroaki; Marshall, Wallace F (2015) Efficient live fluorescence imaging of intraflagellar transport in mammalian primary cilia. Methods Cell Biol 127:189-201 |
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