Award details

Control of cell fate decisions by dynamic signalling filopodia

Reference	BB/V015060/1
Principal Investigator / Supervisor	Professor Hilary Ashe
Co-Investigators / Co-Supervisors	Dr Shukry James Habib
Institution	The University of Manchester
Department	School of Biological Sciences
Funding type	Research
Value (£)	575,604
Status	Current
Type	Research Grant
Start date	01/04/2022
End date	31/03/2025
Duration	36 months

Abstract

The ability of cells to communicate with each other is fundamental to multicellular life. Recently a new concept for cell signalling has emerged with the realization that, rather than diffusing through the extracellular space, signalling molecules are delivered to target cells or received from source cells via signalling filopodia. These filopodia have been described in a number of different cell types, with our recent data showing that Drosophila ovarian germline stem cells (GSCs) synthesise signalling filopodia to receive the BMP self-renewal signal. Additionally, we found that these GSC filopodia can also attenuate BMP signalling, providing the first evidence of signal extinguishing functionality for signalling filopodia. Therefore, the overarching aim of this proposal is to exploit this Drosophila GSC model to determine how signalling filopodia collect and transduce a signal to control cell fate decisions. We will use cutting-edge live imaging to test the role of intrinsic and extrinsic regulators in promoting the directionality of the signalling filopodia towards the stem cell niche. Additionally, we will test different hypotheses relating to how the filopodia extinguish signalling in the GSC to calibrate the signalling response. Finally, as we showed that the differentiating GSC daughters also have filopodia, we will test the hypothesis that these filopodia promote dedifferentiation back to the stem cell fate when GSCs are lost from the niche. The Drosophila ovary is the perfect model for this study, due to its rapid development, amenability to manipulation, suitability for live imaging and the wealth of tools available to study BMP pathway components. Overall, results from this study will not only answer key questions relating to how filopodia regulate signal reception, but our findings on dedifferentiation will be important to the regenerative medicine field, for example in relation to loss of stem cell homeostasis upon aging or due to environmental factors.

Summary

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.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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