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生物，细胞通过发送信号相互通信，这些信号导致接收细胞改变它们成为的细胞类型，即它们的命运。虽然最初认为这种信号在细胞外空间中扩散，直到它们到达接收细胞，但最近已经表明，接收细胞可以延伸手指状突起或丝状伪足，以直接收集来自源细胞的信号。因此，这些类型的“信号丝状伪足”是一种思考细胞通讯的新方式。我们的研究使用经典模型果蝇来研究信号丝状伪足，因为它发育迅速，非常适合遗传学和基因组工程。此外，在人类发育和组织稳态过程中使用的相同信号在果蝇中也被发现，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，它是几乎所有器官和组织发育所必需的。我们研究果蝇生殖系干细胞（GSC），这是持续的卵子生产的关键，并代表了一个强大的模型研究干细胞。卵巢中其他细胞释放的BMP对于维持干细胞命运至关重要。我们最近的研究表明，这些GSC产生信号丝状伪足来收集BMP信号，当GSC分裂时，一个子细胞作为GSC保留，而另一个分化成不同的细胞类型。我们还检测到信号丝状伪足的分化细胞在卵巢，但其功能是完全未知的。我们令人兴奋的假设是，丝状伪足存在于分化中的细胞上，以便在需要时收集BMP信号，诱导它们恢复为干细胞，称为去分化。虽然去分化在体内至关重要，例如在损伤后的组织修复期间，但很难研究。在这里，我们将利用果蝇模型，作为诱导去分化回GSCs的实验策略已被描述。在这个建议中，我们的目标是确定信号丝状伪足如何允许接收BMP信号，进而如何影响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，这将使我们能够对信号丝状伪足进行成像，并在几个小时内定位蛋白质，以回答三个关键问题。首先，信号丝状伪足如何到达它们的靶细胞以收集信号？其次，丝状伪足如何控制细胞内信号的数量？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？总的来说，我们的数据将提供重要的新信息，这一新概念的细胞信号，通过信号丝状伪足。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，通过确定信号丝状伪足在介导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受损组织和器官再生的改进策略。