Morphological control of cell fate, behaviour and function

Tissue formation critically depends on the appropriate assignment of specialised cell fates and behaviours. The traditional perspective of these competitive decisions is that cells first perceive extrinsic signalling cues, decide their fate and then act appropriately (i.e. "decide then act"). However, we propose a much more dynamic "act then decide" view of collective decision-making that exploits the phenomenon of sensorimotor-feedback to temporally modulate the selection process. For example, in response to signalling cues, cells often change shape and extend membrane processes (such as filopodia) that perceive the extracellular environment, placing signal receptors ever closer to signal ligand and creating positive-feedback. Such sensorimotor-feedback operates within minutes without necessitating much slower gene expression changes, hence may dramatically temporally modulate cell decision-making, and is already a well-recognised concept in robotics and child development. However, roles for cell shape in the control of cell signalling, fate and function remain unexplored.

To define dynamic interrelationships between cell morphology and behaviour, this project will:

(a) Probe the impact of cell shape changes on cell signalling dynamics in-vivo. To explore roles for sensorimotor-feedback in the coordination of tissue formation, we will first test if changes in cell morphology correlate with switches in cell signalling dynamics. Using the vertebrate vasculature as a model morphogenetic system (due to its high tractability and close links to cardiovascular disease and cancer), critical cell fate-determining signal networks will be monitored using dynamic fluorescent reporters and advanced in-vivo live imaging approaches in zebrafish embryos. When combined with quantitative morphometric analyses of vascular cell morphology, we will uniquely explore and define interrelationships between dynamic changes in key cell morphological metrics (e.g. cell size, shape, surface area, filopodia extension, cell-cell contacts) and resulting switches in signalling network behaviour (e.g. positive-feedback, signal amplification, noise reduction and oscillations).

(b) Determine if in-vivo manipulation of cell morphology can direct cell fate decisions. In parallel, we will functionally test the role of cell shape dynamics in controlling cell fate and behaviour. Using pharmacological and/or novel optogenetic approaches to manipulate cell shape (e.g. modulation of filopodial dynamics), we will explore the mechanistic impact of switches in cell morphology on vascular signalling network dynamics, cell fate and vascular morphogenesis in-vivo. Hence, we will directly test if changes in cell shape play critical roles in temporally modulating cell signalling and decision-making by sensorimotor-feedback; a novel concept that could potentially be exploited therapeutically to tackle pathological vessel growth in cardiovascular disease and cancer.

As such, this project closely aligns with the core BBSRC DTP theme of studies encompassing 'world class underpinning biosciences'. Moreover, this project will adopt a highly multidisciplinary approach that not only exploits a broad range of core bioscience skills (spanning molecular, cell, developmental and cardiovascular biology) but also integrates cutting-edge computational and in-vivo live bioimaging techniques that will develop key expertise and novel tools in these ground-breaking niche research disciplines. Thus, this project aims to generate innovative research tools and exploit multiple 'new ways of working' (both in-vivo and in-silico) to explore the morphological mechanisms controlling cell fate, behaviour and function in the vasculature.