Zebrafish, in contrast to mammals, regenerate spinal motor neurons. Previous work on spinal-lesioned adult zebrafish has led to important insights into the signals that allow spinal progenitor cells to produce new motor neurons after injury and in human embryonic stem cell culture. In order to replace animal experiments with a substantial severity banding and to significantly speed up experiments, we suggest to develop protocols for spinal lesions in larval zebrafish, most of which are completed before larvae become protected under the Animals (Scientific Procedures) Act 1986. We hypothesise that larval spinal lesion paradigms reproduce the salient features of adult lesions and lead to the discovery of differentiation pathways that are relevant for human stem cell differentiation. Therefore, the PhD student will 1) demonstrate that pathways known from adult regeneration have similar effects in larval regeneration; 2) establish a genetic lesion paradigm for motor neurons; 3) test pathways that are effective in zebrafish motor neuron regeneration and in motor neuron differentiation from human embryonic stem cells. This project will lead to the replacement of up to 400 fish currently undergoing procedures of substantial severity in our laboratory alone, and has the potential to reduce the number of CNS procedures (420,000 per year) overall. Data from this project will improve our understanding of vertebrate motor neuron (re-) eneration, and may ultimately contribute to therapeutic approaches to motor neuron disease and spinal cord injury.
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