Optical based technologies to uncover the role of the protein, Willin/FRMD6, in mammalian neurodevelopment and neurodegeneration.

How the mammalian system develops and works under normal physiological conditions is still not understood. Though many biochemical pathways have been identified to be involved in this process, maybe surprisingly, new ones are still being discovered. We have recently identified a new signal transduction pathway, that has normally been thought to have a role in the development of organs and potentially cancer, is now also involved in neuronal development and potentially neurodegeneration. Specifically, we identified a protein, Willin/FRMD6, which we first discovered as part of the Hippo signalling pathway (Angus et al., 2012), is able to influence the growth and development of neuronal cells. It appears it does this via activating the MAP Kinase pathway. In addition, utilising a novel optical based technology called ERISM (Elastic Resonator Interference Stress Microscopy) that was developed in the School of Physics in St Andrews, we can measure accurately the pico-newton forces that cells make on their substrate. Using this technique, we have very recently shown that Willin/FRMD6 can influence as well, the biophysical properties of cells (Kronenberg et al., 2020).

In this project, we wish to extend our studies into looking at the effects of Willin/FRMD6 on primary neuronal differentiation but also synaptic activity. To uncover the latter question, we will use another novel optical based technology which we have developed, where we can measure the connectivity of a neuronal network in a new high throughput optogenetics technique (Afshar Saber et al., 2018). Specifically, we can measure calcium activity in neurons using what we have called the “OptoCaMP” which combines a novel combination of optogenetics with an optical calcium readout. We will also utilise our bespoke advanced optical microscopy that we have previously developed which includes novel light sheet and super-resolution microscopy. By utilising this blend of cutting-edge optical technology, we will be able to identify how Willin/FRMD6 can change neuronal development and activity. An additional significance is that recently Willin/FRMD6 has also been shown to be potentially involved in neurodegeneration processes, as such our studies will under-pin the fundamental understanding of the mechanisms in play. As indicated above, the successful candidate will develop a wide range of interdisciplinary skills from primary neuronal culturing (including brain slice), through to biochemistry and advanced optical technologies.

Applications can be made online via our online portal- https://www.st-andrews.ac.uk/study/apply/postgraduate/research/