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Epigenetic and transcriptional mechanisms mediating neuronal plasticity

Epigenetic and transcriptional mechanisms mediating neuronal plasticity

Supervisor: Dr Matthias Landgraf


Project summary:

The ability of neurons to adjust to changes in their connectivity and excitation levels is fundamental to nervous system development and function, e.g. learning. We recently discovered novel essential regulators for this plasticity in the nervous system: reactive oxygen species (ROS).

ROS are produced as a metabolic byproduct of mitochondrial ATP synthesis and by NADPH oxidases at the plasma membrane. How ROS signals implement plastic changes in nerve cells remains largely unclear. Interestingly, in other systems the activity and localisation of several transcription factors are regulated by redox modifications. Oxidative stress has been shown to lead to chromatin changes that in turn change expression levels of a range of genes, though whether activity regulated ROS signal similarly through epigenetic changes of chromatin state remains to be seen.

Here, we take advantage of genetic tools that allow us to work with identified motorneurons, their target muscles in the periphery and their connectivity partners in the CNS. We monitor responses to both acute and chronic changes in neuronal activity, induced in intact or semi-intact (pharmacologically accessible) preparations.

What the student will be doing:

In this project you will work with a range of Drosophila preparations, ranging from larvae for behavioural analysis to semi-intact neuromuscular preparations or dissected nerve cords for high resolution single neuron imaging. Using a combination of genetic and immunofluorescent indicators for DNA damage and changes in chromatin state will allow us to determine the impacted of activity-generated ROS on nuclear DNA. Transcriptional profiling will identify candidate genes, whose significance we will investigate in terms of structural plasticity and function, using behavioural paradigms.

References:

1.     Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Morarach K, Sweeney ST and Landgraf M. (2017). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity.  Preprint  bioRxiv 081968.  DOI: dx.doi.org/10.1101/081968     

2.     Milton, V. J. et al. Oxidative stress induces overgrowth of the Drosophila neuromuscular junction. Proc Natl Acad Sci U S A 108, 17521–17526 (2011).

3.    Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci 17, 357–366 (2014).

4.    Couton L., Mauss A.S., Yunusov T., Diegelmann S., Evers JF., Landgraf M. Development of connectivity in a motoneuronal network in Drosophila larvae. Curr Biol. 25:568-76 (2015).  doi: 10.1016/j.cub.2014.12.056.

5.     Oswald, M. C. W., Garnham, N., Sweeney, S. T., & Landgraf, M. (2018). Regulation of neuronal development and function by ROS. FEBS Letters. http://doi.org/10.1002/1873-3468.12972