In Vivo Gene Delivery of STC2 Promotes Axon Regeneration in Sciatic Nerves
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In Vivo Gene Delivery of STC2 Promotes Axon Regeneration in Sciatic Nerves Yewon Jeon 1 & Jung Eun Shin 2 & Minjae Kwon 1 & Eunhye Cho 1 & Valeria Cavalli 3,4,5 & Yongcheol Cho 1 Received: 14 May 2020 / Accepted: 29 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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 injuryresponsive gene required for axon regeneration and a potential target for developing therapeutic applications. Keywords Stc2 . Stanniocalcin 2 . Axotomy . Regeneration . Degeneration . Calcium ion
Abbreviations AU Ax AAV CM DRB DRG HDAC5 HDAC5nuc
arbitrary unit axotomy adeno-associated virus conditioned medium 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside dorsal root ganglion histone deacetylase 5 histone deacetylase 5, nuclear retention mutant form
HIF-1 Iono KD KO NS PNS ShRNA SOCE Wk WT
hypoxia-inducible factor 1 ionomycin knockdown knockout not significant peripheral nervous system short hairpin RNA store-operated calcium entry week wild type
Yewon Jeon and Jung Eun Shin contributed equally to this work.
Introduction
* Yongcheol Cho [email protected]
Axons are susceptible to both physical and non-physical injury that can induce neuronal degeneration and death [1]. However, sensory neurons in the dorsal root ganglions (DRGs) have the potential to reconstruct their axons and recover their function [2, 3]. This is mediated by injuryresponsive transcriptomic changes leading to a physiological shift from a naïve to a growing state [4–9]. Therefore, identifying the genes responsible for the self-defensive mechanisms employed by sensory neurons is important for understanding the protective process of the nervous system, leading to the development of novel therapeutic applications [10, 11]. Stanniocalcin (STC) is a hormonal protein originally discovered in fish that has two variant forms in mammals, STC1
1
Department of Life Sciences, Lab of Axon Regeneration & Degeneration, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 02841, Republic of Korea
2
Department of Molecular Neuroscience, Dong-A University College of Medicine, Busan 49201, Republic of Korea
3
Department of Neuroscience, Washington University School of Medicine, St.
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