The role of the descending dopaminergic projection in spinal development and regeneration

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Nerve cells (neurons) in the spinal cord may be lost after injury. In motor neuron diseases, motor neurons in the spinal cord also die, leading to progressive paralysis and death. The reason for the irreversibility of these conditions is that in the human spinal cord, stem cells fail to regenerate neurons. In contrast, we have shown that the zebrafish regenerates motor neurons and other neurons even in adults. It is therefore important to elucidate the signals that allow these animals such formidable tasks. We have recently described that a messenger molecule, dopamine, is able to augment the generation of motor neurons in zebrafish and in human embryonic stem cells in cell culture, indicating a degree of similarity of this signal between zebrafish and humans. Here we want to find out whether dopamine acts only on stem cells that generate motor neurons and which signals inside the stem cells, responsible for motor neuron generation, are involved. Moreover, we will determine how this dopamine signal allows correct movement patterns of the embryo to emerge during development and whether dopamine can be harnessed to improve swimming function after a loss of motor neurons. Our research thus aims to find new cascades of molecular signals that may be important to understand how the spinal cord in vertebrates develops and how these developmental signals can be re-deployed after injury or degenerative neuron loss, which may ultimately inform cell replacement therapies in injured or diseased patient spinal cords. Moreover, our research indicates that psycho-active drugs that act on dopamine signalling during critical phases of embryonic development may lead to permanent changes in spinal cord function of the embryo. This may inform future research into potentially harmful consequences of drug use during early stages of pregnancy.