Integration of tissue mechanics and cell signalling in developmental patterning of the skin

该项目旨在了解组织机械和细胞信号传导过程如何整合，以产生胚胎发育中细胞命运的重复模式。重点是皮肤，一个有两个组成部分的器官：一个连续的细胞层称为表皮，覆盖着一个松散的细胞层称为真皮。这种类型的复合结构涉及在含有分散和运动细胞的基质顶部的细胞片，在广泛的器官中发现，包括肠、肺、肾、乳腺和唾液腺。这些器官几乎总是由一种复杂的小的重复结构元素组成。这个建议集中在鸟类皮肤中的重复元素，羽毛毛囊，而在其他器官中，重复可以产生分支树，或手指状突起，以获得更大的表面积。有新的证据表明，这些和其他结构不仅是由细胞信号相互作用和局部细胞运动形成的，而且还由细胞产生和响应的特征不佳的机械和物理输入形成。我们对细胞行为的机械影响的大部分知识来自对分离细胞进行的培养实验，缺乏复杂组织环境的背景。本项目将使用快速发育的鸡胚皮肤来定义局部组织环境中的物理差异，确定这些物理差异是如何产生和调节的，并确定它们对细胞间通讯、命运决定和模式形成的影响。我们将使用鸡胚皮肤进行项目，因为它体积大，易于操作，用于跟踪和调节发育过程的合适遗传系的可用性，以及发育事件发生的早期胚胎阶段，避免在实验中使用动物。从迄今为止所做的实验中，我们知道细胞运动、细胞信号和组织拉伸/压缩是羽毛产生及其特定间隔排列的关键。我们将使用最近生成的鸡系，允许可视化和操纵细胞和工程方法，以询问这些过程如何与协同驱动胚胎模式形成的机械/物理变化相结合。

The project aims to understand how tissue mechanical and cell signalling processes are integrated to produce repeating patterns of cell fates in embryonic development. The focus is on the skin, an organ with two constituents: a continuous sheet of cells called the epidermis covering a looser arrangement of cells called the dermis. This type of composite structure that involves a sheet of cells on top of a matrix containing scattered and motile cells is found in a wide range of organs, including the intestine, lung, kidney, and mammary and salivary glands. Such organs are almost invariably composed of an intricate pattern of small repeating structural elements. This proposal focuses on the repeated elements in the avian skin, the feather follicles, while in other organs the repetition can produce a branched tree, or fingerlike projections, to attain a greater surface area. There is emerging evidence that these and other structures are formed not only from cell signalling interactions and local cell movement, but also by poorly-characterised mechanical and physical inputs which are generated by and responded to by cells. Much of our knowledge on mechanical influences on cell behaviours comes from culture experiments performed on isolated cells, absent the context of a complex tissue environment. This project will use the rapidly developing chicken embryonic skin to define the physical differences in local tissue environment, identify how these physical differences arise and are regulated, and determine their effects on intercellular communication, fate determination and pattern formation.We will use chicken embryonic skin for the project due to its large size, ease of manipulation, the availability of suitable genetic lines for tracking and modulating developmental processes, and the early embryonic stage at which developmental events take place, avoiding use of animals in experimentation. From experiments done to date we know that cell motion, cell signalling, and tissue stretching/compression are together key to the production of feathers and their specific spacing arrangement. We will use recently generated lines of chicken allowing visualisation and manipulation of cells and engineering approaches to ask how these processes are integrated with the mechanical/physical changes that cooperate to drive embryonic pattern formation.