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Genetic mechanisms of central nervous system regeneration in Drosophila

rimary Supervisor: Professor Alicia Hidalgo, School of Biosciences

Secondary supervisor: Dr Yun Fan

PhD project title: Genetic mechanisms of central nervous system regeneration in Drosophila

University of Registration: University of Birmingham

Project outline:

The brain changes throughout life, as we experience, learn, adapt and age. Exercise and learning increase plasticity, whilst homeostatic processes occur during sleep. Despite its ability to undergo change, the human central nervous system (CNS) – including brain or spinal cord - does not regenerate upon injury or disease, resulting in devastating disability. Partly, the homeostatic mechanisms that keep the brain stable also prevent the brain from recovering. Nevertheless, some animals can regenerate their CNS. If we could understand what enables them to regenerate and what enables the human CNS to undergo change, we might be able to promote regeneration and repair after injury or disease. Regenerating animals induce neurogenesis, leading to the production of new neurons. Thus, a key approach is to find out how to induce regenerative neurogenesis, perhaps by reprogramming glia into neural stem cells or neurons, and test whether new neurons can project axons and dendrites, integrate into neural circuits and enable recovery of behaviour.

We tackle this big question by aiming to discover underlying genetic mechanisms and investigate the interaction between gene networks, cell biology, neuronal activity, neural circuits and behaviour – after CNS injury. With these methods, we aim to understand how to direct CNS regeneration.

We will use the fruit-fly Drosophila as a model organism, as it is the most powerful genetic model organism. Drosophila genetics has for nearly a century provided ground-breaking discoveries of immense relevance for human health. Drosophila research so far has resulted in six Nobel Prizes, ranging from the discovery of the chromosomal basis of inheritance, to the genetic basis of the body pattern, the universal mechanism of innate immunity and biological clocks. The Drosophila genome was the first complex genome to be sequenced. All the fruit-fly neural circuits are currently being mapped, way ahead of the mapping of human circuits. There are cutting edge genetic and molecular (e.g. CRISPR/Cas9 gene editing) tools to visualise and manipulate neurons and glia, neural circuits, genes, neuronal activity, in vivo, not in a dish, and visualise how this changes behaviour. Investigating CNS injury and repair in fruit-flies does not raise ethical issues.

My team and I established pioneering methods to investigate regeneration in Drosophila and discovered an evolutionarily conserved gene network for glial regeneration. We showed that manipulating these genes in glia alone can shift the response to CNS injury from prevention to promotion of repair. We also found that manipulating glia had a surprising beneficial effect in neuronal repair, and we wish to discover what this positive, regenerative function of glia for neurons is. Studying regeneration in vivo in the fruit-fly Drosophila we will discover fundamental principles that will in the longer-term guide how to promote CNS regeneration in humans.

Objective:

To investigate genetic mechanisms of central nervous system regeneration in the fruit-fly Drosophila.

Methods:

We will use a combination of injury and regeernation experiments with genetics, molecular cell biology including CRISPR/Cas9 gene editing technology and transgenesis, microscopy, including laser scanning confocal microscopy and calcium imaging in time-lapse, computational imaging approaches for analysis of images and movies, stimulating neuronal function with opto- and thermos-genetics in vivo, and recording and analysing fruit-fly behaviour.

References:

  1. http://www.biosciences-labs.bham.ac.uk/hidalgo/Alicia_Hidalgo_Lab_Home.html
  2. Li G and Hidalgo A (2020) Adult neurogenesis in the Drosophila brain: the evidence and the void. International Journal of Molecular Sciences 21(18), 6653
  3. Li G, Forero MG, Wentzell JS, Durmus I, Wolf R, Anthoney NC, Parker M, Jiang R, Hasenauer J, Strausfeld NJ, Heisenberg M, Hidalgo A (2020) A Toll-receptor map underlies structural brain plasticity eLife, 9:e52743 DOI: 10.7554/eLife.52743
  4. See also: “How experience shapes the brain” https://elifesciences.org/digests/52743/how-experience-shapes-the-brain
  5. Anthoney N, Foldi I and Hidalgo A (2018) Toll and Toll-like receptor signalling in development. Development, 145, dev156018. Doi:10.1242/dev.156018
  6. Kato K, Losada-Perez M, Hidalgo A (2018) The gene network underlying the glial regenerative response to central nervous system injury. Developmental Dynamics DOI 10.1002/dvdy.24565
  7. Hidalgo A and Logan A (2017) Go and stop signals for glial regeneration. Current Opinion in Neurobiology 47, 182-187
  8. Losada-Perez, Harrison, Hidalgo (2016) Molecular mechanism of central nervous system repair by the Drosophila NG2 homologue kon-tiki. Journal of Cell Biology 214 (5) 587-601.
  9. Kato K, Forero MG, Fenton JC and Hidalgo A (2011) The glial regenerative response to central nervous system injury is enabled by Pros-Notch and Pros-NFkB feedback. PLoS Biology 9: e1001133

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour

    Techniques that will be undertaken during the project:

    • Molecular biology: cloning, PCR, CRISPR/Cas9 gene editing

    • Genetics: transgenesis, generation of mutants, knock-outs and knock-ins, reporter lines to visualise cells eg with GFP, etc.

    • Cell biology: to test for protein-protein interactions, eg co-immunoprecipitations

    • Microscopy: laser scanning confocal microscopy, epi-fluorescence microscopy, time-lapse including calcium imaging using GcAMP reporters

    • Opto and thermogenetics to manipulate neuronal activity: increase or inhibit neuronal activity and see the consequences with cell biology, GcAMP and behaviour

    • Behaviour: locomotion, optomotor response, learning and memory

    Contact: Professor Alicia Hidalgo, University of Birmingham