Biomechanics of Tissue Motility

摘要 在神经系统发育过程中，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到 他们周围的环境来推动自己前进。体外研究已经确定了三种- 细胞如何在底物上移动的阶跃机制：细胞向 迁徙，附着在底物上，背部分离。体内的细胞是否使用 同样的运动机制尚不清楚，因为实验限制阻碍了 类似的研究。该项目将解决这一挑战，并结合一种新的蛋白质 利用高分辨率成像提供空间和时间控制的耗尽方法 询问组织如何在活着的动物体内向前推进。对于这些研究，我们将使用 斑马鱼后侧线原基迁移作为脊椎动物模型系统的研究 因为它对强大的基因扰动和成像具有适应性。为了揭示 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的 细胞向前，焦点粘连是否通过细胞传递产生的力 对周围环境的收缩，以及周围环境对摩擦力的反应。 由于RhoA信号和焦点黏附成分在人类中是保守的，所以 拟议的研究将为更好地建模和理解提供必要的背景 发育中的神经系统缺陷和纠正这些缺陷的策略。

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.