Biomechanics of Tissue Motility

摘要 在神经系统发育期间，细胞和组织经常移动以组装成 层和簇。要做到这一点，细胞需要产生力并将力传递给 周围的环境来推动自己前进。体外研究已经确定了三个- 细胞如何在基板上移动的步进机构：细胞在 迁移，粘附到衬底上并在背面分离。体内细胞是否使用 同样的机制移动是不清楚的，因为实验的局限性阻碍了 类似的研究。这个项目将解决这一挑战，并联合收割机一种新的蛋白质 耗尽方法，提供高分辨率成像的时空控制 来研究活体动物的组织是如何向前推进的。对于这些研究，我们将使用 作为脊椎动物模型系统的斑马鱼后侧线原基迁移 因为它对强大的遗传扰动和成像的顺从性。揭示 迁移原基中力产生和传递的分子基础， 将决定RhoA脉冲是如何产生的，RhoA诱导的细胞收缩是如何拉动 细胞向前，是否局灶性粘连通过细胞传递产生的力 收缩到周围环境以及周围环境如何响应摩擦力。 由于RhoA信号传导和粘着斑组分在人类中是保守的， 拟议的研究将提供必要的背景，以更好地建模和理解 发育神经系统缺陷，并告知策略，以纠正这些缺陷。

ABSTRACT During nervous system development, cells and tissues often move to assemble into layers and clusters. To do this, the cells need to generate force and transmit force to their surroundings to push themselves forward. In vitro studies have identified a three- step mechanism for how cells move on a substrate: cells protrude in the direction of migration, adhere to the substrate and detach in the back. Whether cells in vivo use the same mechanism to move is unclear because experimental limitations have hindered similar studies. This project will address this challenge and combine a novel protein depletion approach that offers spatial and temporal control with high resolution imaging to ask how a tissue pushes itself forward in a living animal. For these studies, we will use the zebrafish posterior lateral line primordium migration as a vertebrate model system because of its amenability to powerful genetic perturbations and imaging. To reveal the molecular basis of force generation and transmission in the migrating primordium, we will determine how RhoA pulses are generated, how RhoA-induced cell contractions pull cells forward, whether focal adhesions transmit the force generated through cell contractions to the surroundings and how the surroundings respond to the friction force. Since RhoA signaling and focal adhesion components are conserved in humans, the proposed studies will provide necessary context to better model and understand developmental nervous system defects and inform strategies to correct these defects.