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Lumenogenesis: Understanding fluid flow into a closed cavity

Presented by: 
Kishore Mosaliganti Harvard University
Thursday 17th September 2015 - 11:30 to 12:30
INI Seminar Room 1
Co-authors: Ian Swinburne (Harvard Medical School), Sean Megason (Harvard Medical School) 

Most internal organs including the eyes, lung, gut, kidney, bladder, brain, and vascular system, all begin as epithelialized cysts or tubes with a fluid-filled lumen. Developmental growth of these tissues is regulated by the transepithelial fluid transport. In the zebrafish inner ear, recent work in the Megason Lab showed that transepithelial flow creates hydrostatic pressure in the lumen, which in turn, inhibits fluid transport rates to control overall vesicle growth rate. As a first step to linking pressure forces to transport mechanisms, the origin, path, and physical mechanism underlying fluid movement needs to be identified. Quantitative imaging shows that extracellular, but not intracellular, fluid is transported from basal to apical ends of the epithelium. Dye-tracing experiments revealed localization patterns of dye in paracellular spaces indicative of the movement of fluid. To verify if fluid flow is coupled with dye patterns, we developed a mathematical model that s howed that advective dye movement is sufficient to explain experimental outcomes. In general, the transport of salts and fluid across an epithelium occurs via electrogenic pumps/transporters and aquaporins on cell membranes, or paracellularly through cell-cell junctions. However, in "leaky" epithelia, it is not clear how such gradients can be sustained to drive rapid transport of fluid for growth. Previous work in the otic vesicle identified the activity of Na-K-ATPase in setting up a spontaneous electrical potential to drive the selective movement of water and ions. However, we show that Na-K channels are uniformly expressed throughout the cell membrane and their expression levels drop before the period of rapid growth. Using state-of-the-art light-sheet microscopy, we show new visualizations of pulsatile fluid movement through paracellular spaces. Thus, our current data suggests that other, as yet unknown, intermediate cellular mechanisms could facilitate the unidirectional movement of fluid.
University of Cambridge Research Councils UK
    Clay Mathematics Institute London Mathematical Society NM Rothschild and Sons