Mammals cannot repair their central nervous system (CNS, brain and spinal cord) after injury or in neurodegenerative disease. Our group is using the amazing capacity of the zebrafish to regenerate their spinal cords and in particular motor neurons to elucidate the molecular and cellular mechanisms underlying functional repair of the CNS.
In the translucent zebrafish embryo, the entire motor system can be visualized and studied. In this image of an embryo 24 hours post fertilisation, TH expressing fibers (red) project into the spinal cord close to the cell bodies of motor neurons (green).
Zebrafish have an amazing capacity for central nervous system (CNS) regeneration. They regain function after complete lesions of the spinal cord or the optic nerve. Such lesions in mammals are not repaired and functions are permanently lost. We therefore ask:
- How can zebrafish replace lost neurons from adult stem cells?
- How do motor neurons establish their axons and how is this important in motor neuron disease?
To address these questions we are focusing on spinal motor neurons, which are important target cells for axons descending from the brainstem that control swimming movements. We have shown that regeneration of descending axons is necessary for functional recovery after a spinal lesion and are now investigating the signals that lead to the (re-)generation of motor neurons. We have found that in embryonic motor neurons, transcriptional co-factors control expression of specific cell recognition molecules, such as chondrolectin, which in turn are necessary for pathfinding of embryonic motor axons. We are now using genetic and small molecule screens to discover new factors that are important for motor neuron differentiation, both during development and adult regeneration.
By analysing development and regeneration of important cell types in the zebrafish we hope to gain insight into fundamental developmental and regenerative mechanisms in the CNS, and to ultimately increase our understanding of human conditions, such as spinal cord injury and motor neuron disease.
- Wellcome Trust
- Ingolf Bach, University of Massachusetts Medical School
- Siddharthan Chandran, The Euan MacDonald Centre for Motor Neurone Disease Research
- Tom Gillingwater, University of Edinburgh
- David Lyons, University of Edinburgh
- Dirk Sieger, University of Edinburgh
- Keith Sillar, University of St. Andrews
- Kevin Talbot, University of Oxford
- Will Talbot, Stanford University
- Anna Williams, CRM, Edinburgh