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，细胞通过发送信号来彼此通信，这些信号会导致接收细胞改变其命运的细胞类型。虽然最初认为这种信号在细胞外空间中扩散直到到达接收单元，但最近已经表明，一个接收单元可以延伸像投影或丝状的手指，以直接从源单元中收集信号。因此，这些类型的“信号传导丝状”是一种关于细胞通信的新方法。我们的研究研究使用经典模型，果蝇果蝇（Fruitfly Drosophila）发达，这很快就会发育，并且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期间使用的相同信号在果蝇中也发现它们对于发育也是必不可少的。骨形态发生蛋白（BMP）是细胞信号的主要类型，这对于几乎所有器官和组织的发展都是必需的。我们研究果蝇种系干细胞（GSC），这对于持续产卵至关重要，代表了研究干细胞的强大模型。卵巢中其他细胞释放的BMP对于维持干细胞命运至关重要。我们最近的数据表明，这些GSC使信号传导丝状疾病收集BMP信号。当GSC划分时，一个女儿保持为GSC，而另一个女儿则将其区分为另一种细胞类型。我们还检测到卵巢中分化细胞上的信号传导丝状虫，但它们的功能是完全未知的。我们令人兴奋的假设是，丝状虫存在于区分细胞上，因此可以在需要时收集BMP信号，该信号诱导它们恢复为干细胞，称为DEDIDFEFFERTIDITION。虽然去分化在体内至关重要，例如在受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，作为一种实验策略，以诱导DeDiventiation返回GSC。在此提案中，我们旨在确定信号传导丝毫允许如何接收BMP信号，从而如何影响GSC行为。为了实现这一目标，我们将使用最新的显微镜方法，这将使我们能够一次数小时的信号传导丝状和蛋白质的定位来回答三个关键问题。首先，信号传导丝状如何到达其目标细胞以收集信号？其次，丝状如何控制细胞内部的信号传导量？第三，在需要时，是否会在需要时收集BMP信号的信号传导丝状症？总的来说，我们的数据将通过信号丝状丝虫来提供与此新概念有关的重要新信息。我们的发现将与其他干细胞系统广泛相关，因为已经表明，不同类型的干细胞还使用信号丝状虫收集信号。此外，通过确定信号传导丝状疾病在介导回干细胞命运中的作用，我们的数据最终将有助于改善损坏组织和器官再生的策略。