Supracellular synchronization of actomyosin contractility during collective neural crest cell durotaxis

集体神经嵴细胞杜罗轴过程中肌动球蛋白收缩力的细胞上同步

• 批准号: 513518868
• 负责人: Dr. Kai Weissenbruch
• 金额: --
• 依托单位: Department of Cell and Developmental Biology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513518868?language=en
• 关键词: Supracellular; synchronization; actomyosin; contractility; during

Collective cell migration is a highly coordinated process during development, regeneration and metastasis formation. Neural crest cells, an invasive mesenchymal cell population, collectively migrate not only in response to chemical factors but also along stiffness gradients in the underlying substratum, a process called durotaxis. Collective durotaxis requires extraordinary levels of mechanosensing, symmetry breaking, intercellular communication and synchronized actomyosin contraction, to coordinate a directional supracellular movement. However, how collectively migrating neural crest cells communicate, in order to synchronize their protrusive and force-generating machineries across several cell borders during durotaxis, is still not understood. Using Xenopus embryos as a model system, we seek to decipher these processes by investigating the synergy of force-generating nonmuscle myosin II paralogs, intercellular communication via gap junctions, and calcium propagation, in vitro and in vivo. In my PhD research, I showed that in vitro, the intrinsic features of the nonmuscle myosin II paralogs A and B complement each other during force generation and morphogenesis of single cells. While paralog A provides rapid tugging forces, necessary to initiate the contractile machinery throughout the cell body, paralog B gradually stabilizes pre-initiated contractions in subcellular regions to autonomously generate a polarized actomyosin network across the cell body. Although this concept can explain the morphogenesis of individual migrating cells, in this project I hypothesize that similar principles can be applied to explain collective durotaxis in vivo of multicellular neural crest cell cluster. To investigate the pathway that mediates synchronized actomyosin contraction across multiple adjacent cells, we will focus on intercellular communication via gap junctions, transmembrane channels that connect the cytoplasm of adjacent cells, allowing exchange of signalling molecules and ions. Preliminary data from the host lab suggest that gap junctions are involved in collective neural crest migration. We will unravel if gap junctional intercellular communication mediates the synchronization of the contractile machinery and how it influences the generation of a polarized actomyosin network, considering the distinct nonmuscle myosin II paralogs. In order to identify possible signals that could be propagated via gap junctions and influence the actomyosin cytoskeleton, we will focus on calcium ions and IP3-mediated calcium release from internal stores. Calcium is a well-known actomyosin stimulator and preliminary data from the host lab suggest that IP3 is involved in calcium signalling during collective neural crest migration. We expect that this multidisciplinary project will provide answers to a central yet unresolved question: how individual cells are coordinated during collective cell migration.

集体细胞迁移是发育、再生和转移形成过程中高度协调的过程。神经嵴细胞是一种侵袭性间充质细胞群，不仅会响应化学因素，还会沿着底层基质的硬度梯度集体迁移，这一过程称为杜罗轴（durotaxis）。集体杜罗轴需要非凡水平的机械传感、对称性破坏、细胞间通讯和同步肌动球蛋白收缩，以协调定向细胞上运动。然而，集体迁移的神经嵴细胞如何进行通信，以便在杜罗轴过程中跨多个细胞边界同步其突出和产生力的机器，目前仍不清楚。使用非洲爪蟾胚胎作为模型系统，我们试图通过研究体外和体内产生力的非肌肉肌球蛋白 II 旁系同源物、通过间隙连接的细胞间通讯以及钙传播的协同作用来破译这些过程。在我的博士研究中，我表明，在体外，非肌肉肌球蛋白 II 旁系同源物 A 和 B 的内在特征在单细胞的力生成和形态发生过程中相互补充。旁系同源物 A 提供启动整个细胞体收缩机制所必需的快速拉力，而旁系同源物 B 逐渐稳定亚细胞区域中预先启动的收缩，以自主生成跨细胞体的极化肌动球蛋白网络。虽然这个概念可以解释单个迁移细胞的形态发生，但在这个项目中，我假设类似的原理可以应用于解释多细胞神经嵴细胞簇体内的集体杜罗轴。为了研究介导跨多个相邻细胞同步肌动球蛋白收缩的途径，我们将重点关注通过间隙连接的细胞间通讯，间隙连接是连接相邻细胞细胞质的跨膜通道，允许信号分子和离子的交换。来自宿主实验室的初步数据表明间隙连接参与集体神经嵴迁移。考虑到不同的非肌肉肌球蛋白 II 旁系同源物，我们将阐明间隙连接细胞间通讯是否介导收缩机制的同步，以及它如何影响极化肌动球蛋白网络的生成。为了识别可能通过间隙连接传播并​​影响肌动球蛋白细胞骨架的信号，我们将重点关注钙离子和 IP3 介导的内部储存钙释放。 Calcium is a well-known actomyosin stimulator and preliminary data from the host lab suggest that IP3 is involved in calcium signalling during collective neural crest migration.我们期望这个多学科项目将为一个尚未解决的核心问题提供答案：个体细胞在集体细胞迁移过程中如何协调。