Patterning of ciliated epithelia by mechanical strain

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Project Summary Ciliated epithelia produce directed fluid flow that is critical for human organ formation and function. One of the key outstanding questions in the field is how these epithelia acquire a planar axis required for cilia orientiation or positioning, thus directing ciliary flow in an appropriate way for function. This issue is particularly important in the context of the left-right patterning, where a flow-based mechanism operates within a structure called the left-right organizer (LRO). Flow produced in the LRO breaks symmetry along the left-right body axis, and defects in this process is thought to be a leading cause of heterotaxy in humans, including in the etiology of congenital heart defects. To achieve flow-based patterning, cilia are positioned along the anterior-posterior (A-P) planar axis of LRO cells, causing a tilt that results in leftward flow but how this axis is initially aligned to the A-P body axis is unknown. Recently, mechanical strain has emerged as an important global cue that directs the axis of planar polarity in epithelia with multiciliated cells, raising the possibility that mechanical cues also direct the formation of the LRO. Indeed, in preliminary studies, mechanical strain was found to not only pattern the planar axis of the Xenopus LRO, but also the formation of motile cilia, and cilia location. The impact of mechanical strain on the LRO will be studied using imaging approaches and experimental manipulations that perturb the patterns of strain in the embryo. Together, these studies will provide new insights into how mechanical strain can act as a multifaceted cue to direct key features required for flow-based patterning of the left-right axis, and how mechanical perturbations in the embryo can lead to birth defects.