Regulation of axon regeneration by the RNA repair/splicing pathway

Mechanisms governing a neuron’s regenerative ability are important but not well understood. We identified Rtca, RNA 3′-terminal phosphate cyclase, as an inhibitor for axon regeneration. Removal of dRtca cell-autonomously enhanced axon regrowth in the Drosophila central nervous system, whereas its overexpression reduced axon regeneration in the periphery. Rtca along with the RNA ligase Rtcb and its catalyst Archease operate in the RNA repair/splicing pathway important for stress induced mRNA splicing, including that of Xbp1, a cellular stress sensor. dRtca and dArchease had opposing effects on Xbp1 splicing, and deficiency of dArchease or Xbp1 impeded axon regeneration in Drosophila. Moreover, overexpressing mammalian Rtca in cultured rodent neurons reduced axonal complexity in vitro, whereas reducing its function promoted retinal ganglion cell axon regeneration after optic nerve crush in mice. Our study thus links axon regeneration to cellular stress and RNA metabolism, revealing new potential therapeutic targets for treating nervous system trauma. Reprints and permissions information is available at www.nature.com/reprints. Readers are welcome to comment on the online version of the paper. Correspondence and requests for materials should be addressed to Y.N.J ([email protected]). 4Present address: Allen Institute for Brain Science, Seattle, WA 98103 5Present address: Weill Institute for Cell and Molecular Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853 The authors declare no competing financial interests. AUTHOR CONTRIBUTIONS Y.S. carried out most of the experiments and performed the data analysis. D.S. performed the optic nerve crush experiment, E.A.S. performed LacZ staining, J.B. performed Rtca expression analysis, X.H. contributed to the neuronal culture experiment, T.C. contributed to the RGC axon regeneration analysis, X. X. performed the motor axon regeneration assay, S.M. contributed to the stress assay, C.H. made the UAS-dRtca fly strain, T.N. contributed to the optic nerve crush experiment, J.C.B. and M.S.B. contributed to the mouse axon regeneration experiment, Y.S., L.Y.J. and Y.N.J. together conceived the research and wrote the manuscript. SUPPLEMENTARY INFORMATION Online Methods Supplementary Figures 1–15 Supplementary References (43–54) HHS Public Access Author manuscript Nat Neurosci. Author manuscript; available in PMC 2015 December 01. Published in final edited form as: Nat Neurosci. 2015 June ; 18(6): 817–825. doi:10.1038/nn.4019. A uhor M anscript