Every cell in an embryo starts as a blank slate, but within days, some commit to becoming heart, brain, or gut—and no one fully understands how that first decision is made. This project tackles a fundamental gap: scientists know how to keep stem cells in their flexible, pluripotent state, but they have almost no grasp of the earliest molecular triggers that push them toward a specific fate. The researcher will use a new screening method to identify the proteins that kick-start differentiation, then track those proteins in real time inside living mouse embryos and lab-grown embryo models. By simultaneously measuring changes in cell adhesion, shape, and gene activity, the work aims to reveal the hidden rules that make one cell turn into a neuron while its neighbour becomes skin. This is fundamental science—there is no immediate medical or commercial application. But understanding how cells reliably choose their identities is the bedrock of future regenerative medicine, where the goal is to manufacture replacement tissues or organs on demand. Similar curiosity-driven work on developmental biology has already underpinned advances in stem-cell therapies and organoid technology.
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Whilst considerable progress has been made in understanding the factors that establish and maintain pluripotency, little is known about the earliest events that drive pluripotent cells towards particular differentiated fates. I will build on a screening strategy developed in my lab to discover novel pro-differentiation transcriptional regulators. These will be exploited as markers to identify, monitor, and interrogate cells taking the first steps towards their choice of differentiated cell t ype, and provide us with new tools for transcriptional programming. I will exploit these new markers of early cell transitions in order to uncover the transcriptional networks that stabilise alternative cell states and generate differences between individual cells in the way they respond to particular differentiation cues. I will investigate how these novel pro-differentiation factors operate. In particular, I will test the hypothesis that changes in cell adhesion and tissue morphogenesis directly regulate differentiation, and I will explore the underlying mechanisms. I will develop tools to allow multiple events (differentiation, cell adhesion and spatial organisation of cells, signalling pathway activity) to be manipulated and quantitatively monitored simultaneously, both in early embryos and in vitro models of early development. Using these tools, I will identify the 'missing links' in our understanding of developmental decisions, uncovering the interplay between transcript ion, signalling, and morphogenesis. My ultimate aim is to discover the hidden rules behind the apparent unpredictability of the differentiation response.
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