The establishment of an orderly neuronal circuitry is essential for proper organismal development and function. This is a highly complex process involving the coordinated and guided growth of neurites (projections emanating from neuronal cell body) to establish connections between neurons themselves and with other tissues. Central to this is the polarization of the neurite and the assembly of cellular factors that promote their polarized outgrowth. The aim of this project is to understand how polarity pathways drive downstream molecular events responsible for neurite extension within a developing neuron. Understanding the mechanisms underlying neural circuitry formation will provide insights into the molecular basis of neurological and neurodegenerative disorders.
This project will focus on the role of the PAR polarity complex, notably Par3, Par6 and aPKC during neurite outgrowth. Par polarity has been linked to neurite polarization, but how Par proteins regulate polarization is highly unclear. A well-established downstream effector of the Par complex in several other contexts is the microtubule cytoskeletal machinery. What are the downstream effectors of the Par complex in developing neurons? Microtubules are integral to neurite function and also essential for dendritic extension (Cheerambathur et al., 2019) and the Par complex has been shown to be enriched at the tips of growing dendrites of sensory neurons and essential for dendrite extension in C. elegans (Fan et al., 2019).
The goal of this project is to determine how the Par polarity complex influences the microtubule machinery to promote neurite outgrowth using C. elegans and Drosophila as model systems. To tackle this problem, the project will draw on the expertise of the Cheerambathur Lab in mechanistic analysis of the microtubule cytoskeleton during neuronal development and that of the Januschke Lab in dynamics of cell polarisation and chemical genetics (Hannaford et al., 2019).
The student will engineer and develop visualization tools (e.g. cytoskeletal, polarity and neuronal cell specific markers) to assess the morphological and cytoskeletal changes associated with neurite extension. These tools will then be used in conjunction with genetic approaches (e.g. loss of function alleles, chemical genetics) to determine the relation of polarity complex and the microtubule network in several contexts including neurite extension. The student will also be trained state-of-the-art in vivo high-resolution live microscopy, image analysis tools (e.g. Image J), genetics and molecular biology techniques. Taken together, the student will develop experience in quantitative cell biology using the latest genetic and imaging tools to tackle questions related to neuronal development. Additionally, this collaborative effort will allow the student to work in labs with complementing expertise and access the state-of-the-art research and training environment offered by the two institutions, the Wellcome Centre for Cell Biology in Edinburgh and the School of Life Sciences in Dundee.
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Cheerambathur, D.K., Prevo, B., Chow, T.-L., Hattersley, N., Wang, S., Zhao, Z., Kim, T., Gerson-Gurwitz, A., Oegema, K., Green, R., et al. (2019). The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis. Dev. Cell.
Fan, L., Kovacevic, I., Heiman, M.G., and Bao, Z. (2019). A multicellular rosette-mediated collective dendrite extension. Elife .
Hannaford, M, Ramat, A., Loye, N. and Januschke, J. (2018). aPKC-mediated displacement and actomyosin-mediated retention polarize Miranda in Drosophila neuroblasts. Elife
How good is research at University of Edinburgh in Biological Sciences?
FTE Category A staff submitted: 109.70
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