Control of cell fate decisions by dynamic signalling filopodia

通过动态信号丝状伪足控制细胞命运决定

• 批准号: BB/V015060/1
• 负责人: Hilary Ashe
• 金额: $ 73.34万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV015060%2F1
• 关键词: Control; cell; fate; decisions; dynamic

In order for a fertilised egg to develop into a multicellular organism, cells communicate with each other by sending signals that cause receiving cells to change the type of cell they become, i.e. their fate. While it was originally thought that such signals diffuse in the extracellular space until they reach the receiving cell, recently it has been shown that instead a receiving cell can extend a finger like projection, or filopodium, to directly collect the signal from the source cell. Therefore, these type of 'signalling filopodia' are a new way of thinking about cellular communication. Our research studies signalling filopodia using the classic model, the fruitfly Drosophila, as it develops quickly and is very amenable to genetics and genome engineering. Moreover, the same signals that are used during human development and tissue homeostasis are found in the fruitfly where they are also essential for development. Bone Morphogenetic Proteins (BMPs) are one of the major types of cell signals, which are necessary for development of nearly all organs and tissues. We study Drosophila germline stem cells (GSCs), which are critical for continued egg production and represent a powerful model for studying stem cells. BMPs released by other cells in the ovary are critical for maintaining the stem cell fate. Our recent data show that these GSCs make signalling filopodia to collect the BMP signal.When the GSC divides, one daughter stays as a GSC whereas the other differentiates into a different cell type. We have also detected signalling filopodia on the differentiating cells in the ovary, but their function is completely unknown. Our exciting hypothesis is that the filopodia exist on differentiating cells so that they can, when required, collect the BMP signal which induces them to revert back to a stem cell, called dedifferentiation. While dedifferentiation is critically important in the body, for example during tissue repair following injury, it is difficult to study. Here we will exploit the Drosophila model, as an experimental strategy for inducing dedifferentiation back to GSCs has been described.In this proposal we aim to determine how the signalling filopodia allow receipt of the BMP signal and in turn how this influences GSC behaviour. To achieve this goal we will use state-of-the-art microscopy approaches, which will allow us to image the signalling filopodia and the localization of proteins on them for hours at a time, to answer three key questions. Firstly, how do the signalling filopodia reach their target cells to collect the signal? Secondly, how do the filopodia control the amount of signalling inside the cell? Thirdly, do the signalling filopodia on differentiating cells collect the BMP signal to promote dedifferentiation when required?Overall our data will provide important new information in relation to this new concept for cell signalling, via signalling filopodia. Our findings will be broadly relevant to other stem cell systems, as it has been shown that different types of stem cells also use signalling filopodia to collect signals. Moreover, by identifying a role for signalling filopodia in mediating dedifferentiation back to a stem cell fate, our data will ultimately be useful in the development of improved strategies for the regeneration of damaged tissues and organs.

为了使受精卵发育成多细胞有机体，细胞之间通过发送信号相互通信，这些信号使接收细胞改变它们成为的细胞类型，即它们的命运。虽然最初认为这些信号在细胞外空间扩散，直到它们到达接收细胞，但最近的研究表明，接收细胞可以伸展手指状突起或丝状基座，直接从源细胞收集信号。因此，这些类型的“信令丝状伪足”是一种新的思考细胞通讯的方式。我们的研究使用经典模型果蝇研究丝状伪足的信号，因为它发育迅速，非常容易受到遗传学和基因组工程的影响。此外，在果蝇中也发现了在人类发育和组织动态平衡过程中使用的相同信号，它们对发育也是必不可少的。骨形态发生蛋白(BMPs)是细胞信号的主要类型之一，几乎对所有器官和组织的发育都是必需的。我们研究果蝇生殖系干细胞(GSCs)，这对持续的卵子生产至关重要，并代表了研究干细胞的强大模型。卵巢中其他细胞释放的BMPS对于维持干细胞的命运至关重要。我们最近的数据显示，这些GSC制造信令丝状基孔来收集BMP信号。当GSC分裂时，一个女儿仍然是GSC，而另一个分化成不同的细胞类型。我们还在卵巢中的分化细胞上检测到了信号丝状足细胞，但它们的功能完全未知。我们令人兴奋的假设是，丝状足细胞存在于分化细胞上，因此当需要时，它们可以收集BMP信号，诱导它们恢复到干细胞，称为去分化。尽管去分化在体内至关重要，例如在损伤后的组织修复过程中，但很难进行研究。在这里，我们将利用果蝇模型，因为已经描述了一种诱导去分化回到GSC的实验策略。在这个建议中，我们的目标是确定信号丝状通道如何允许BMP信号的接收，以及这反过来如何影响GSC的行为。为了实现这一目标，我们将使用最先进的显微镜方法，这将使我们能够一次成像信号丝状伪足和蛋白质在其上的定位数小时，以回答三个关键问题。首先，信号丝状伪足是如何到达它们的目标细胞来收集信号的？其次，丝状伪足是如何控制细胞内的信号量的？第三，分化细胞上的信号丝状伪足是否在需要时收集BMP信号以促进去分化？总体而言，我们的数据将通过信号丝状伪足提供与这一细胞信号新概念相关的重要新信息。我们的发现将广泛地与其他干细胞系统相关，因为已经表明不同类型的干细胞也使用信号丝状伪足来收集信号。此外，通过确定丝状足细胞在调节去分化回到干细胞命运中的作用，我们的数据最终将有助于开发改进的受损组织和器官再生策略。