Mechanical and Other Directional Signals Controlling Vertebrate Planar Cell Polarity

在过去的25年里，我们在获取胚胎细胞并通过生物化学方法引导它们成为一系列不同的特定细胞类型的能力方面取得了巨大的进步。这一知识使我们能够利用这些细胞来修复或替换体内受损或患病的细胞。该领域的医学进步被称为“再生医学”，用作起始材料的细胞类型被称为“干细胞”，我们在这些方面的专业知识建立在基本发育生物学的基础上。下一个前沿是超越对细胞类型的控制，并开始理解复杂组织和结构的组装——“形态发生”——因为组织的结构对它们的功能至关重要。为了达到这种理解，有必要把形态发生分解成它的组成过程。一个这样的过程是收敛扩展（CE），其中组织通过其细胞的自组织定向重排而变窄和变长。这个过程需要一组称为Wnt-PCP通路的分子的功能。Wnt是一种可溶分子，可以在组织中扩散，它被认为为CE中重排的方向提供了一个长期的方向性线索。然而，有迹象表明，Wnt可能不是线索，或者不是唯一的线索：在果蝇胚胎和一些非洲爪蟾（包括我们自己的胚胎）的研究表明，机械力可以使细胞内CE和PCP分子的方向对齐。该项目将测试(1)自组织或外部施加的机械力是否使组织中的CE对齐，(2)不同类型的组织边界本身是否可以为CE提供方向线索，以及(3)Wnt本身是否可以在有或没有机械力的情况下重新定位CE。总之，这些实验将给我们一个很好的想法，关于CE通常是如何定向的，因此我们如何控制它的方向，最终使组织结构的雕刻为再生医学的目的。

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.