Epigenetic and transcriptional mechanisms mediating neuronal plasticity
Supervisor: Dr Matthias Landgraf
The ability of neurons to adjust to changes in their connectivity and excitation levels is fundamental to nervous system development and function. We recently discovered that motorneurons asssess their activity, at least in part, by measuring levels of reactive oxygen species (ROS) produced as a metabolic byproduct of mitochondrial ATP synthesis. Other studies have shown that transcription is a necessary part of learning, memory and structural adjustments. Interestingly, the activity and localisation of several transcription factors are regulated by redox modifications, and oxidative stress has been shown to lead to chromatin changes that in turn change expression levels of a range of genes.
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 use a combination of genetic and immunofluorescent indicators for DNA damage, euchromatin and heterochromatin, and determine to what extent oxidative stress vs. activity generated ROS induce changes in the DNA. Followed up by transcriptional profiling we would aim to focus on a small number of candidate genes and mechanisms. The project will take full advantage of the intricate genetic reagents with which to visualise and manipulate specific motorneurons, their target muscles or pre-motor interneurons. A combination of semi-intact preparations (for pharmacological manipulations) or intact animals (manipulated using thermo- and opto-genetics) will be used for live imaging to determine the dynamics of structural adjustments.
1. 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).
2. Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat Neurosci 17, 357–366 (2014).
3. 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.
4. Tripodi, M., Evers, J. F., Mauss, A., Bate, M. & Landgraf, M. Structural homeostasis: compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input. PLoS Biol 6, e260 (2008).