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In Vivo Gene Delivery of STC2 Promotes Axon Regeneration in Sciatic Nerves

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Abstract

Neurons are vulnerable to injury, and failure to activate self-protective systems after injury leads to neuronal death. However, sensory neurons in dorsal root ganglions (DRGs) mostly survive and regenerate their axons. To understand the mechanisms of the neuronal injury response, we analyzed the injury-responsive transcriptome and found that Stc2 is immediately upregulated after axotomy. Stc2 is required for axon regeneration in vivo and in vitro, indicating that Stc2 is a neuronal factor regulating axonal injury response. The application of the secreted stanniocalcin 2 to injured DRG neurons promotes regeneration. Stc2 thus represents a potential secretory protein with a feedback function regulating regeneration. Finally, the in vivo gene delivery of STC2 increases regenerative growth after injury in peripheral nerves in mice. These results suggest that Stc2 is an injury-responsive gene required for axon regeneration and a potential target for developing therapeutic applications.

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Abbreviations

AU:

arbitrary unit

Ax:

axotomy

AAV:

adeno-associated virus

CM:

conditioned medium

DRB:

5,6-dichlorobenzimidazole 1-β-D-ribofuranoside

DRG:

dorsal root ganglion

HDAC5:

histone deacetylase 5

HDAC5nuc:

histone deacetylase 5, nuclear retention mutant form

HIF-1:

hypoxia-inducible factor 1

Iono:

ionomycin

KD:

knockdown

KO:

knockout

NS:

not significant

PNS:

peripheral nervous system

ShRNA:

short hairpin RNA

SOCE:

store-operated calcium entry

Wk:

week

WT:

wild type

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Funding

This work was supported by the Health Technology R&D Project (HI17C1459) through the Korea Health Industry Development Institute (KHIDI), funded by the Korean Ministry of Health & Welfare and supported by a Korea University Grant to Y.C., by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIT) 2016R1A5A2007009 to J.E.S.

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Author notes

  1. Yewon Jeon and Jung Eun Shin contributed equally to this work.

Authors and Affiliations

  1. Department of Life Sciences, Lab of Axon Regeneration & Degeneration, Korea University, Anam-ro 145, Seongbuk-gu, Seoul, 02841, Republic of Korea

    Yewon Jeon, Minjae Kwon, Eunhye Cho & Yongcheol Cho

  2. Department of Molecular Neuroscience, Dong-A University College of Medicine, Busan, 49201, Republic of Korea

    Jung Eun Shin

  3. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Valeria Cavalli

  4. Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Valeria Cavalli

  5. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Valeria Cavalli

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  1. Yewon Jeon
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  2. Jung Eun Shin
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  3. Minjae Kwon
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  4. Eunhye Cho
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  5. Valeria Cavalli
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  6. Yongcheol Cho
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Contributions

J.E.S., V.C., and Y.C. designed the research; J.E.S., Y.J., M.K., E.C., and Y.C. conducted the research; and J.E.S., V.C., and Y.C. wrote the manuscript.

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Correspondence to Yongcheol Cho.

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Jeon, Y., Shin, J.E., Kwon, M. et al. In Vivo Gene Delivery of STC2 Promotes Axon Regeneration in Sciatic Nerves. Mol Neurobiol 58, 750–760 (2021). https://doi.org/10.1007/s12035-020-02155-2

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