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

在所有由不止一个细胞组成的生物体的发育过程中，有效的细胞交流对于从单个受精的卵细胞发育到复杂的成年身体至关重要。细胞之间的交流是建立细胞类型多样性的基础，形成组织和器官，最终形成整个有机体。我们目前对细胞信号传递的理解中最基本的原则之一是，信号由一组细胞产生，另一组接收。产生细胞产生一个信号，接收细胞使用特定的受体蛋白检测到该信号。然后，该信号的检测导致接收器单元中的信令网络被激活，从而导致行为改变。WNT蛋白是这些协调细胞行为的基本信号分子中的一类。WNTs调节许多关键的细胞过程，因此对早期生命的发育至关重要。WNT信令网络中一个重要的信号通路是WNT/PCP。WNT/PCP通过调节细胞的速度、方向性和粘附性来协调细胞和组织的迁移。WNT/PCP还可以控制细胞层内细胞的极性，以控制细胞延伸的位置和方向，如纤毛、刚毛和毛发。因此，Wnt/PCP信号对胚胎发育和器官发育至关重要。然而，在我们对Wnt/PCP通路如何发挥作用的理解上仍有很大的差距。在为这一提议做准备的过程中，我们揭示了Wnt信号存在一种意想不到的细胞间转运机制。特定的指状细胞膜突起-也称为细胞素-携带Wnt蛋白并将其输送到邻近细胞。Wnt细胞线的形成障碍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育异常。因此，了解控制细胞素的系统对于了解Wnt如何在胚胎发生和成人组织自我调节中发挥作用是基本的。这一独特的知识将为操纵Wnt蛋白运输以控制再生和疾病中Wnt信号级联的活动提供基础。我们的建议将解决我们对WNT/PCP信令理解中的两个关键差距：(1)如何将WNT/PCP信号从一个细胞传递到另一个细胞；(2)如何将传递的消息转化为细胞响应。基于导致这一提议的初步工作，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，活性的Wnt/PCP配体-受体复合体沿着这些细胞质转运，并被转移到受体细胞以调节信号转导。了解这一机制至关重要，因为这意味着细胞可以对Wnt/PCP信号做出反应，即使它们不表达相关的受体。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，并将使我们能够发展出胚胎发育过程中信号传递的高级概念。

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.