Molecular interactions of receptor complexes regulating cell migration and axon guidance

On the surface of each cell in your body, receptors guide and regulate the cell’s function and movement, depending on the signal molecules around it.

These receptors can relay signals that instruct malfunctioning cells (e.g. cancerous) to die, but under less fortunate circumstances also induce their spread (metastasis). They also regulate e.g. inflammation and tissue regeneration.

While prevention of cancer metastasis and control over inflammation and wound healing is very desirable, alterations to signalling pathways is fraught danger and potential side-effects without knowing their fundamental mechanisms. The Neogenin receptor and its constituent signal molecules Netrin and RGM exemplify this.

They are a staple in axon pathfinding and key regulators in many physiological contexts. Curiously, Netrin and RGM evoke opposite cellular responses through the Neogenin receptor. We do not know how this proceeds, preventing its safe pharmacological targeting. The mechanism by which its co-receptor UNC5 alters the Neogenin response is also unknown.

I will combine cutting-edge techniques in protein production, characterization, and cryo electron microscopy to obtain molecular snapshots of complexes and to determine the interactions responsible for signal activation of Neogenin by Netrin, RGM and UNC5.

This will help explain how molecular signals are converted to a cellular response, and provide a solid foundation for future design of therapies that can target many human afflictions.