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Regulation of axon regeneration by the RNA repair and splicing pathway

Nature Neuroscience volume 18, pages 817825 (2015) | Download Citation

Abstract

Mechanisms governing a neuron's regenerative ability are important but not well understood. We identify Rtca (RNA 3′-terminal phosphate cyclase) as an inhibitor of axon regeneration. Removal of Rtca cell-autonomously enhanced axon regrowth in the Drosophila CNS, 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 and splicing pathway important for stress-induced mRNA splicing, including that of Xbp1, a cellular stress sensor. Drosophila Rtca and Archease had opposing effects on Xbp1 splicing, and deficiency of Archease 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.

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Acknowledgements

We thank S. Younger, S.K. Ultanir, S. Yadav, D. Wang, S. Barbel, M. Tynan-La Fontaine and J. Sacramento for technical assistance; J. Martinez for advice on the Rtca pathway; I. Hariharan (University of California, Berkeley), T. Xu (Yale) and H.D. Ryoo (New York University) for fly lines; the Bloomington Stock Center, Kyoto Drosophila Genetic Resource Center (DGRC), Vienna Drosophila Resource Center (VDRC) and Exelixis for fly stocks; DGRC for plasmids; UCSF ES Cell Targeting Core for generating the knockout mouse; and members of the Jan laboratory for discussions. Y.S. is a recipient of a National Institute of Neurological Disorders and Stroke (NINDS) Pathway to Independence Award. This work was supported by a NINDS K99/R00 award (1K99NS088211-01) to Y.S., a National Science Foundation Graduate Research Fellowship (1144247) to S.M., a UC Irvine-Roman Reed Spinal Cord Injury grant (P0045665) to Y.N.J., a NIH grant (2R37NS040929) to Y.N.J., a NIH grant (EY010688-19) to D.S. and a Research to Prevent Blindness grant to D.S. L.Y.J. and Y.N.J. are investigators of Howard Hughes Medical Institute.

Author information

Author notes

    • Jim Berg

    Present address: Allen Institute for Brain Science, Seattle, Washington, USA.

    • Chun Han

    Present address: Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA.

Affiliations

  1. Howard Hughes Medical Institute, University of California, San Francisco, California, USA.

    • Yuanquan Song
    • , Jim Berg
    • , Xi Huang
    • , Tong Cheng
    • , Xin Xiong
    • , Shan Meltzer
    • , Chun Han
    • , Lily Yeh Jan
    •  & Yuh Nung Jan
  2. Department of Physiology, University of California, San Francisco, California, USA.

    • Yuanquan Song
    • , Jim Berg
    • , Xi Huang
    • , Tong Cheng
    • , Shan Meltzer
    • , Chun Han
    • , Lily Yeh Jan
    •  & Yuh Nung Jan
  3. Department of Ophthalmology, University of California, San Francisco, San Francisco, California, USA.

    • David Sretavan
    •  & Trong-Tuong Nguyen
  4. Brain and Spinal Injury Center, University of California, San Francisco, California, USA.

    • Ernesto A Salegio
    • , Jacqueline C Bresnahan
    •  & Michael S Beattie

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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 β-galactosidase 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-Rtca fly strain; T.-T.N. contributed to the optic nerve crush experiment; J.C.B. and M.S.B. contributed to the mouse axon regeneration experiment; and Y.S., L.Y.J. and Y.N.J. together conceived the research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yuh Nung Jan.

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https://doi.org/10.1038/nn.4019

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