Mechanical and Other Directional Signals Controlling Vertebrate Planar Cell Polarity

点击翻译按钮获取中文摘要

In the past twenty-five years there has been dramatic progress in our ability to take embryonic cells and guide them biochemically to become a range of different specific cell types. This knowledge promises to allow us to use such cells to repair or replace damaged or diseased cells in the body. Medical advances in this area are known as "regenerative medicine" and the types of cells used as the starting material are called "stem cells" and our expertise with these has been built on a foundation of basic developmental biology. The next frontier is to go beyond control of cell type and begin to understand the assembly of complex tissues and structures - "morphogenesis" - since it is the architecture of tissues that is critical for their function. To achieve this understanding it is necessary to break down morphogenesis into its constituent processes. One such process is convergent extension (CE) in which tissue narrows and lengthens by self-organised directional rearrangement of its cells. This process requires the function of a set of molecules referred to as the Wnt-PCP pathway. Wnt is a soluble molecule that can diffuse through tissue and it has been thought that it provides a long-range directional cue for the direction of rearrangements in CE. However, there are hints that Wnt may not be the cue, or not the only cue: work in Drosophila fly embryos and some in Xenopus, including our own, has suggested that mechanical force can align the orientation of CE and PCP molecules within cells. This project will test (1) whether mechanical force, either self-organised or externally applied, aligns CE in tissues, (2) whether tissue boundaries of different types can themselves provide the orientation cues for CE and (3) whether Wnt itself can re-orientate CE with or without mechanical force. Together these experiments will give us a good idea about how CE is normally orientated and therefore how we might control its orientation ultimately to enable the sculpting of tissue architectures for the purposes of regenerative medicine.