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Retinoic acid receptor β2 promotes functional regeneration of sensory axons in the spinal cord

Abstract

The embryonic CNS readily undergoes regeneration, unlike the adult CNS, which has limited axonal repair after injury. Here we tested the hypothesis that retinoic acid receptor β2 (RARβ2), critical in development for neuronal growth, may enable adult neurons to grow in an inhibitory environment. Overexpression of RARβ2 in adult rat dorsal root ganglion cultures increased intracellular levels of cyclic AMP and stimulated neurite outgrowth. Stable RARβ2 expression in DRG neurons in vitro and in vivo enabled their axons to regenerate across the inhibitory dorsal root entry zone and project into the gray matter of the spinal cord. The regenerated neurons enhanced second-order neuronal activity in the spinal cord, and RARβ2-treated rats showed highly significant improvement in sensorimotor tasks. These findings show that RARβ2 induces axonal regeneration programs within injured neurons and may thus offer new therapeutic opportunities for CNS regeneration.

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Figure 1: RARβ2 enhances neurite outgrowth from DRG neurons via the activation of cAMP signaling pathways.
Figure 2: DRG neurite extension in spinal cord coculture.
Figure 3: EIAV-mediated gene transfer in the spinal cord and DRG.
Figure 4: Axonal regeneration of injured sensory neurons across the DREZ.
Figure 5: Peripheral afferent stimulation activates postsynaptic neurons in the spinal cord.
Figure 6: RARβ2 promoted functional recovery after axonal regeneration.

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Acknowledgements

We thank M. Agudo for help with the synthesis of the RARβ2 riboprobe, E. Foster for help with DRG cultures and L. Walmsley for technical help. This work was supported by Oxford BioMedica and the Medical Research Council.

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Correspondence to Liang-Fong Wong or Nicholas D Mazarakis.

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Competing interests

This Research has been funded by Oxford BioMedica. L.F.W., M.A., S.M.K., A.J.K and N.D.M. are employees of Oxford BioMedica.

Supplementary information

Supplementary Fig. 1

Morphology and inflammatory response in the rat spinal cord after vector injection. (PDF 4400 kb)

Supplementary Fig. 2

Increased cAMP immunoreactivity in EIAV-RARβ2 transduced DRG neurons. (PDF 2296 kb)

Supplementary Fig. 3

Comparison of functional recovery between EIAV-RARβ2 and cAMP-treated animals (PDF 1591 kb)

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Wong, LF., Yip, P., Battaglia, A. et al. Retinoic acid receptor β2 promotes functional regeneration of sensory axons in the spinal cord. Nat Neurosci 9, 243–250 (2006). https://doi.org/10.1038/nn1622

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