Challenging cellular competence: Spreading of active ligand-receptor complexes by cytonemes

在所有由一个以上细胞组成的生物体的发育过程中，有效的细胞通讯对于从单个受精卵细胞发育成复杂的成体至关重要。细胞间的通讯是建立细胞类型多样性、形成组织和器官以及最终形成整个生物体的基础。我们目前对细胞信号传导的理解的最基本原则之一是，信号由一组细胞产生，并由另一组细胞接收。生产者细胞产生信号，该信号由接收者细胞使用特定的受体蛋白检测。然后，该信号的检测导致接收器小区中的信令网络的激活，从而引起行为的改变。Wnt蛋白是一类协调细胞行为的重要信号分子。Wnt调节许多关键的细胞过程，因此对早期生命的发展至关重要。Wnt信号网络中的一个重要信号通路是Wnt/PCP。Wnt/PCP通过调节细胞速度、方向性和粘附来协调细胞和组织的迁移。Wnt/PCP还可以决定细胞层内细胞的极性，以控制细胞延伸物如纤毛、刚毛和毛发的位置和方向。因此，Wnt/PCP信号传导对胚胎发生和器官发育至关重要。然而，我们对Wnt/PCP通路如何发挥作用的理解仍然存在很大的差距。在准备这项提议时，我们揭示了Wnt信号存在一种意想不到的细胞-细胞转运机制。特定的指状细胞膜突起-也称为细胞素-携带Wnt蛋白并将其运输到邻近细胞。Wnt细胞丝体形成的障碍导致发育过程中的严重后果，如组织畸形和严重的胚胎发生异常。因此，了解控制细胞素的系统对于了解Wnt在胚胎发生和成体组织自我调节过程中的功能至关重要。这一独特的知识将为操纵Wnt蛋白转运以控制再生和疾病中Wnt信号级联的活性提供基础。我们的提案将解决我们对Wnt/PCP信号传导理解中的两个关键空白：（1）Wnt/PCP信号如何从一个细胞传递到另一个细胞;（2）传递的信息如何转化为细胞反应。基于导致这一提议的初步工作，我们假设Wnt/PCP信号与生产细胞内的特异性受体结合，从而激活Wnt细胞素的形成。我们进一步假设，活性Wnt/PCP配体-受体复合物被运输沿着这些细胞素，并被转移到接收细胞调节信号。理解这种机制是非常重要的，因为这意味着细胞可以响应Wnt/PCP信号，即使它们不表达相关受体。这一新知识有可能从根本上改变我们对信号产生者和信号接收者的理解，并使我们能够在胚胎发生过程中发展一种先进的信号概念。

During the development of all organisms consisting of more than one cell, effective cellular communication is vital to allow development from a single fertilised egg cell to a complex adult body. Cell-to-cell communication is fundamental to establishing cell-type diversity, forming tissues and organs, and finally, the entire organism. One of the most basic principles of our current understanding of cell signalling is that signals are produced by one group of cells and received by another group. The producer cells generate a signal that is detected by the receiver cells using a specific receptor protein. The detection of this signal then leads to activation of a signalling network in the receiver cells causing a change in behaviour. Wnt proteins are one class of these essential signalling molecules that orchestrate cell behaviour. Wnts regulate many critical cellular processes and are therefore fundamental to the development of early life. A vital signalling pathway within the Wnt signalling network is Wnt/PCP. Wnt/PCP coordinates the migration of cells and tissues by regulating cell speed, directionality, and adhesion. Wnt/PCP can also dictate the polarity of cells within a cell layer to control the position and orientation of cell extensions such as cilia, bristles and hairs. Therefore, Wnt/PCP signalling is fundamental to embryogenesis, and organ development. However, there are still significant gaps in our understanding of how the Wnt/PCP pathway functions.In preparation for this proposal, we have revealed the existence of an unexpected cell-to-cell transport mechanism for Wnt signals. Specific finger-like cell membrane protrusions - also known as cytonemes - carry Wnt proteins and transport them to neighbouring cells. Disturbance in the formation of Wnt cytonemes leads to severe consequences during development such as malformation of tissues and severe embryogenic abnormalities. Therefore, understanding the system that governs cytonemes is fundamental for understanding how Wnt functions during embryogenesis and adult tissue self-regulation. This unique knowledge will provide the foundations to manipulate Wnt protein transport to control the activity of Wnt signalling cascades in regeneration and diseases. Our proposal will address two key gaps in our understanding of Wnt/PCP signalling: (1) How Wnt/PCP signals are delivered from one cell to another and (2) how is the delivered message translated into a cellular response. Based on preliminary work leading up to this proposal, we hypothesise that Wnt/PCP signals bind to specific receptors within the producer cells, which activates the formation of Wnt cytonemes. We further hypothesise that the active Wnt/PCP ligand-receptor complexes are transported along these cytonemes and are transferred to the receiver cell to regulate signalling. Understanding this mechanism is vitally important because it means that cells can respond to Wnt/PCP signals even if they do not express the relevant receptors. This new knowledge has the potential to fundamentally change our understanding of signal producers and signal receivers and will allow us to develop an advanced concept of signalling during embryogenesis.