Dopamine from the Brain Promotes Spinal Motor Neuron Generation during Development and Adult Regeneration

Abstract

Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.

Neuronal Regeneration from Ependymo-Radial Glial Cells: Cook, Little Pot, Cook!

“…Similar to the pro-regenerative effect of dopamine on motor neuron generation in zebrafish (Reimer et al, 2013), in adult mammals, dopamine, serotonin, and other neurotransmitters promote neurogenesis in constitutively active neurogenic zones (Berg et al, 2013). Overall, these examples show that upon closer inspection, unexpected similarities in cell types and signals can be observed between regenerating and non-regenerating vertebrates.…”

“…Dopamine acts on the G protein-coupled D4a receptor and activates the hedgehog pathway via suppression of cyclic AMP/protein kinase A signaling (Reimer et al, 2013). This is recapitulated after a spinal lesion in adults, when spinal ERGs re-express the D4a receptor.…”

“…Because of their robust regenerative powers and the availability of a wide array of molecular-genetic tools, such as expression profiling (Hui et al, 2014;Sehm et al, 2009), genetic cell ablation (Lambert et al, 2012;Reimer et al, 2013), lineage tracing (Kroehne et al, 2011;Skaggs et al, 2014), and genome editing (Auer and Del Bene, 2014;Fei et al, 2014), salamanders and zebrafish provide an ideal system for uncovering mechanisms regulating CNS regeneration. Unbiased analyses of lesioninduced gene regulation will help to elucidate the contribution of known developmental signaling pathways, as well as unknown signals to successful neuronal regeneration.…”

“…Targeted genetic ablation of specific cell types, such as dopaminergic (Lambert et al, 2012) or motor (Reimer et al, 2013) neurons, will help to determine the specific signals that lead to the regeneration of these cells.…”

Neural development and regeneration: it's all in your spinal cord

“…Catherina G. Becker (University of Edinburgh, UK) reported how different neurotransmitters derived from the spinal projections of supraspinal neurons act on these progenitors to control spinal neurogenesis (Reimer et al, 2013) and promote the generation of MNs after a complete spinal cord transection. Osvaldo Chara (ZIH, Dresden, Germany and IFLYSIB, La Plata, Argentina) presented a computational model based on previous ideas (Chara et al, 2014) and used in vivo experimental data on axolotl to show that both proliferation and an influx of ependymal cells are crucial for spinal cord repair.…”