Patterning of ciliated epithelia by mechanical strain

项目摘要 纤毛上皮产生定向的液体流动，这对人体器官的形成和功能至关重要。 该领域的一个关键悬而未决的问题是这些上皮细胞是如何获得平面轴的 纤毛定向或定位，从而以适当的方式引导纤毛流动以发挥作用。这个问题是 尤其重要的是在左右图案的上下文中，其中基于流动的机构运行 在一个称为左-右组织器(LRO)的结构中。LRO中产生的流动破坏了对称性 左-右身体轴，这一过程中的缺陷被认为是导致 人类，包括在先天性心脏病的病因学方面。为了实现基于流动的图案，纤毛是 沿LRO细胞的前后(A-P)平面轴定位，导致倾斜导致向左 流动，但这个轴最初是如何与A-P体轴对齐的尚不清楚。最近，机械应变 作为一个重要的全球线索，它指导着具有多纤毛的上皮细胞的平面极性轴 细胞，增加了机械线索也指导LRO形成的可能性。事实上，在 初步研究发现，机械应变不仅对非洲爪哇LRO的平面轴产生图案， 还可形成可移动的纤毛，并定位纤毛。机械应变对LRO的影响将是 使用成像方法和实验操作来研究，这些方法扰乱了 胚胎。总之，这些研究将为机械应变如何发挥作用提供新的见解。 指向基于流的左右轴图案所需的关键特征的多方面提示，以及如何 胚胎中的机械干扰会导致出生缺陷。

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.