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Coordinating Neuronal Development

Brain stem neurons direct the specification of their spinal cord targets, the motor neurons. For proper control of the locomotor system by the brain, maturation of axons projecting long distances from the brain to their targets, the motor neurons, in the spinal cord must be synchronized (see Kong et al.). Reimer et al. found that dopamine released by diencephalic neurons mediated the specification of motor neurons at the expense of interneurons in the zebrafish spinal cord during development. In situ analysis showed that diencephalic axons were the only source of dopaminergic innervation and that motor neuron progenitors were positive for the D4a dopamine receptor in the embryonic spinal cord. Pharmacological studies, as well as gain- and loss-of-function studies, indicated that dopaminergic signaling through D4a receptors controlled the balance of motor neurons and a specific type of interneuron (V2 interneurons) by promoting the proliferation of the motor neuron progenitor pool and thus differentiation into motor neurons instead of V2 interneurons. D4a receptors are Gi-coupled G protein–coupled receptors and inhibit the production of adenosine 3', 5'-monophosphate (cAMP) and thus protein kinase A (PKA) activity, which attenuates Hedgehog (Hh) signaling. Pharmacological manipulation of cAMP concentrations indicated that reducing cAMP contributed to motor neuron specification in the spinal cord, a response that was mediated by enhancing Hh signaling (measured as increased Hh target gene expression). Furthermore, knockdown of the transcriptional regulator and Hh mediator Gli2b, which is necessary for motor neuron specification, resulted in the loss of motor neurons that could not be rescued by application of a dopamine receptor agonist. Of potential clinical interest, the ability of dopamine to stimulate motor neuron specification was not limited to embryos, and zebrafish with transected spinal cords exhibited a lesion-induced increase in D4a receptor transcripts on the side of the lesion adjacent to the brain (rostral), but not on the distal side (caudal). The rostral side had more newly generated motor neurons than the caudal side, and motor neuron production was lost if dopaminergic axons were specifically ablated with a toxin. However, injection of a dopamine receptor agonist stimulated the increase in D4a receptor transcripts and Hh signaling in the region caudal to the lesion and increased the number of motor neurons without altering the rostral response. Thus, this developmental pathway can be reactivated after spinal cord damage in zebrafish. M. M. Reimer, A. Norris, J. Ohnmacht, R. Patani, Z. Zhong, T. B. Dias, V. Kuscha, A. L. Scott, Y.-C. Chen, S. Rozov, S. L. Frazer, C. Wyatt, S.-i. Higashijima, E. E. Patton, P. Panula, S. Chandran, T. Becker, C. G. Becker, Dopamine from the brain promotes spinal motor neuron generation during development and adult regeneration. Dev. Cell 25, 478–491 (2013). [PubMed] J. H. Kong, S. J. Butler, B. G. Novitch, My brain told me to do it. Dev. Cell 25, 436–438 (2013). [Online Journal]