The mammalian spinal cord does not regenerate motor neurons that are lost as a result of injury or disease. Here we demonstrate that adult zebrafish, which show functional spinal cord regeneration, are capable of motor neuron regeneration. After a spinal lesion, the ventricular zone shows a widespread increase in proliferation, including slowly proliferating olig2-positive (olig2 ϩ ) ependymo-radial glial progenitor cells. Lineage tracing in olig2:green fluorescent protein transgenic fish indicates that these cells switch from a gliogenic phenotype to motor neuron production. Numbers of undifferentiated small HB9 ϩ and islet-1 ϩ motor neurons, which are double labeled with the proliferation marker 5-bromo-2-deoxyuridine (BrdU), are transiently strongly increased in the lesioned spinal cord. Large differentiated motor neurons, which are lost after a lesion, reappear at 6 -8 weeks after lesion, and we detected ChAT ϩ /BrdU ϩ motor neurons that were covered by contacts immunopositive for the synaptic marker SV2. These observations suggest that, after a lesion, plasticity of olig2 ϩ progenitor cells may allow them to generate motor neurons, some of which exhibit markers for terminal differentiation and integration into the existing adult spinal circuitry.
In contrast to mammals, the spinal cord of adult zebrafish has the capacity to reinitiate generation of motor neurons after a lesion. Here we show that genes involved in motor neuron development, i.e., the ventral morphogen sonic hedgehog a (shha), as well as the transcription factors nkx6.1 and pax6, together with a Tg(olig2:egfp) transgene, are expressed in the unlesioned spinal cord of adult zebrafish. Expression is found in ependymoradial glial cells lining the central canal in ventrodorsal positions that match expression domains of these genes in the developing neural tube. Specifically, Tg(olig2:egfp) ϩ ependymoradial glial cells, the adult motor neuron progenitors (pMNs), coexpress Nkx6.1 and Pax6, thus defining an adult pMN-like zone. shha is expressed in distinct ventral ependymoradial glial cells. After a lesion, expression of all these genes is strongly increased, while relative spatial expression domains are maintained. In addition, expression of the hedgehog (hh) receptors patched1 and smoothened becomes detectable in ependymoradial glial cells including those of the pMN-like zone. Cyclopamine-induced knock down of hh signaling significantly reduces ventricular proliferation and motor neuron regeneration. Expression of indicator genes for the FGF and retinoic acid signaling pathways was also increased in the lesioned spinal cord. This suggests that a subclass of ependymoradial glial cells retain their identity as motor neuron progenitors into adulthood and are capable of reacting to a sonic hedgehog signal and potentially other developmental signals with motor neuron regeneration after a spinal lesion.
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