In previous posts I have discussed the importance of comparing similar developmental processes during embryogenesis and regeneration. This is important in order to determine up to what extend regeneration is a mere recapitulation of embryonic development or, on the contrary, it implies different actors. The answer to this question is not probably unique (or white or black) and will depend on the model used and the specific context analysed. The laboratory of Thomas Becker and Catherine Becker has recently published how dopamine promotes the formation of motor neurons both during embryogenesis and adult regeneration in zebrafish (http://www.ncbi.nlm.nih.gov/pubmed/23707737).
As axons descending from the brain to the spinal cord may control proliferation and differentiation of neural progenitors in that spinal cord they focussed on the putative role of brain-derived dopamine. In fact, the only source of dopamine in the spinal cord comes from axons projecting from the diencephalon. First, the authors addressed the function of dopamine in the generation of motor neurons during embryonic development by three independent approaches. In all cases, they found that by decreasing the number of dopaminergic neurons or dopamine production there was a significant decrease in the number of motor neurons in the developing spinal cord. On the contrary, the uses of a dopamine agonist lead to an increase in the number of these motor neurons. They also found that this action of dopamine is mediated by the D4a receptor. At the cellular level, dopamine action seems to expand the pool of motor neuron progenitors. At the molecular level, the activation of the D4a receptor appears to inhibit the cAMP/protein kinase A pathway, which in turn inhibits the Hedgehog (Hh) pathway. The Hh has been shown also to be important for motor neuron differentiation.
Once determined the role of dopamine from descending axons on motor neuron development the authors sought to determine whether dopamine was also required for the regeneration of this neuronal population. It is well known that zebrafish can regenerate their spinal cord upon transection and that Hh pathway is required for it. As in embryos, the only sources of dopamine in adults are descending axons from the brain. Upon complete transection dopaminergic projections and activation of the D4a receptor are mainly detected rostral to the lesion site, which results in many more new motor neurons generated rostral than caudal to the lesion. When these dopaminergic axonal projections were ablated the number of new motor neurons regenerated rostral to the lesion was significantly reduced, pointing out a conserved role of dopamine on regeneration. Remarkably, the application of a dopamine agonist in the caudal site of the lesion (a region in which very little neurogenesis is normally observed) was able to induce the expression of D4a as well as to promote a high increase in the number of motor neurons regenerated. Moreover, the effects of dopamine on motor neuron regeneration appeared to be also mediated through the Hh pathway as happens during development.
In summary, these results suggest that dopamine activates Hh signalling (through inhibiting cAMP-dependent PKA activity) to promote the expansion of the pool of progenitor cells and allow motor neuron generation in two different contexts: embryogenesis and adult regeneration. More importantly, this data opens the possibility that this pathway can be modulated with agonists in order to promote or enhance neural regeneration in other vertebrates.