Patterning of the epithelial planar polarized microtubule cytoskeleton

我们实验室的工作重点是组织形成和图案化过程中的集体细胞行为。特别是，我们的目标是了解局部产生的机械力整合到全球组织力模式中，以及由此导致的细胞和组织形状的变化。在最近的工作中，我们证明了在果蝇发育过程中，基于肌动蛋白的收缩和基于微管的突出力之间的微妙平衡决定了果蝇的翅膀形状(Singh等人，2018年，NAT Cell Biol)。具体地说，我们发现，微管(MT)细胞骨架在单细胞水平的图案化通过协调生成细胞自主的局部力并将其整合到全局组织力模式(集体力学)中来指导组织形态发生。我们进一步证实，MTS以及由此产生的机械细胞和组织属性，对由平面细胞极性(PCP)蛋白质确定的全局线索做出反应而对齐。然而，这一基本过程的确切机制仍然难以捉摸。在拟议的项目中，我们现在将扩展我们之前的研究，并提供关键的见解：·MT细胞骨架如何在发育中的上皮细胞中印记细胞秩序(目标1)。·单个细胞如何通过MTS机械耦合以协调组织形状(目标2)。此外，拟议的研究将确定MT细胞骨架被利用来控制发育过程中的上皮重构的新机制。

Work in our lab is focused on collective cell behavior during tissue formation and patterning. In particular, we aim at understanding the integration of locally produced mechanical forces into a global tissue force pattern and the resulting changes in cell and tissue shape. In recent work, we showed that a delicate balance between actin-based contractile and microtubule-based protruding forces determine wing shape during Drosophila development (Singh et al., 2018, Nat Cell Biol). Specifically, we found that patterning of the microtubule (MT) cytoskeleton at the single cell level instructs tissue morphogenesis via coordinated generation and integration of cell-autonomous local forces into a global tissue force pattern (collective mechanics). We further established that MTs, and in consequence mechanical cell and tissue properties, align in response to global cues determined by planar cell polarity (PCP) proteins. Yet, the precise mechanism for this fundamental process has remained elusive. In the proposed project, we will now extend our previous studies and provide crucial insights into: • How the MT cytoskeleton imprints cellular order in the developing epithelium (Aim 1).• How individual cells are mechanically coupled via MTs to coordinate tissue shape (Aim 2).Together, the proposed studies will identify novel mechanisms by which the MT cytoskeleton is harnessed to control epithelium remodeling during development.