The ability of ciliated epithelia to generate directed fluid flow is an important aspect of diverse developmental and physiological processes including proper respiratory function. To achieve directed flow, ciliated cells must generate 100-200 cilia that are polarized along a common axis both within and between cells. My lab is currently working towards understanding the molecular mechanisms for how cell polarity is coordinated as well as how individual cilia interpret the cells polarity. We have determined that ciliated cells receive polarity cues via the non-cononical Wnt / Planar Cell Polarity (PCP) pathway, but the details of this are still poorly understood. Additionally, the PCP pathway is known to influence a cells cytoskeleton dynamics and a main goal is to understand how this influences the ability of individual cilia to coordinate their polarity.
Centrioles are microtubule based structures with nine fold symmetry that are involved in both centrosome organization and aster formation during cell division. During the normal cell cycle centrioles duplicate once, generating a mother / daughter pair, and in most post-mitotic vertebrate cells the mother centriole then goes on to form the basal body of a sensory cilium. Abnormalities in the duplication of centrioles (and centrosomes) are prevalent in many cancers suggesting a link between centriole duplication and cancer progression. While the field of cell biology has made significant advances in understanding many aspects of centriole biogenesis the factors that limit centriole duplication remain poorly understood. My laboratory is addressing this fundamental question in cell biology from a novel direction with the use of Xenopus motile ciliated cells. Ciliated cells are unique among vertebrate cells in that they generate hundreds of centrioles (basal bodies) therefore providing a great system for studying the regulation of centriole duplication. Understanding how nature has overcome the typically tight regulation of centriole duplication will lend insight into the molecular mechanisms of cancer progression.
Publications:
Liu J, Wu X, Mitchell B, Kintner C, Ding S and Shultz PG (2005). A small-molecule agonist of the Wnt signaling pathway. Angewandte Chemie (Int. Ed. Engl.) 18;44(13):1987-90. (Research Highlight, Nature Chemistry)
Mitchell B, Jacobs R, Li J, Chien S and Kintner C (2007). A positive feedback mechanism governs the polarity and motion of motile cilia. Nature May 3;447(7140):97-101. (Faculty of 1000: Must Read; Research Highlight: Nature Reviews Molecular Cell Biology)
Woodfuff J, Mitchell B, Shankland M (2007). Pax3/7A is an early marker of leech mesoderm involved in segmental morphogenesis, nephridial development, and body cavity formation. Developmental Biology June 15;306(2):824-837.
Park TJ, Mitchell B, Abitua PB, Kintner C and Wallingford JB (2008). Dishevelled controls apical docking and planar polarization of basal bodies in a mucociliary epithelium. Nature Genetics. Jul;40(7):871-9.
