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

在所有由多个细胞组成的生物体的发育过程中，有效的细胞通讯对于使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，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中最基本的原则之一是信号是由一组细胞产生并由另一组细胞接收的。产生细胞产生一个信号，该信号被使用特定受体蛋白的接收细胞检测到。这种信号的检测会激活接收细胞中的信号网络，从而导致行为的改变。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、方向性和粘附性来协调细胞和组织的迁移。Wnt/PCP还可以指示细胞层内细胞的极性，以控制细胞延伸（如纤毛、刚毛和毛发）的位置和方向。因此，Wnt/PCP信号是胚胎发生和器官发育的基础。然而，我们对Wnt/PCP通路如何发挥作用的理解仍然存在重大差距。为了准备这一建议，我们已经揭示了Wnt信号在细胞间传递机制的存在。特定的指状细胞膜突起——也被称为细胞素——携带Wnt蛋白并将其运送到邻近的细胞。Wnt细胞素形成的紊乱会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是理解Wnt在胚胎发生和成体组织自我调节过程中如何发挥作用的基础。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。我们的建议将解决我们对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应答。基于这一建议的初步工作，我们假设Wnt/PCP信号与产生细胞内的特定受体结合，从而激活Wnt细胞素的形成。我们进一步假设，活性Wnt/PCP配体受体复合物沿着这些细胞素运输，并被转移到受体细胞以调节信号传导。了解这一机制至关重要，因为这意味着即使细胞不表达相关受体，它们也可以对Wnt/PCP信号做出反应。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受者的理解，并使我们能够发展出胚胎发生过程中信号传导的先进概念。

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.