Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α

Yongcheol Cho; Jung Eun Shin; Eric Edward Ewan; Young Mi Oh; Wolfgang Pita-Thomas; Valeria Cavalli

doi:10.1016/j.neuron.2015.09.050

Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α

Yongcheol Cho, Jung Eun Shin, Eric Edward Ewan, Young Mi Oh, Wolfgang Pita-Thomas, Valeria Cavalli

Research output: Contribution to journal › Article › peer-review

109 Citations (Scopus)

Abstract

Injured peripheral neurons successfully activate a proregenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re-innervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.

Original language	English
Pages (from-to)	720-734
Number of pages	15
Journal	Neuron
Volume	88
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2015.09.050
Publication status	Published - 2015 Nov 18

Bibliographical note

Funding Information:
We thank Dr. Gidday for helpful discussion and comments on hypoxic conditioning. We thank Dr. DiAntonio for critical reading of the manuscript and sharing DLK knockout mouse line. We thank Marcus Mahar for assistance with bioinformatics. This work was supported in part by National Institutes of Health Grants DE022000 and NS082446, the Hope Center for Neurological Disorders Just In-Time Award, the Hope Center Viral Vectors Core at Washington University School of Medicine, and the University of Missouri Spinal Cord Injuries Research Program (to V.C.); grants by the National Research Foundation of Korea (NRF-2012R1A6A3A03039290 to Y.C.); and the Wings for Life (WFL-US-002/13 to J.E.S.).

Publisher Copyright:
© 2015 Elsevier Inc.

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2015.09.050

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title = "Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α",

abstract = "Injured peripheral neurons successfully activate a proregenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators coordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re-innervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.",

author = "Yongcheol Cho and Shin, {Jung Eun} and Ewan, {Eric Edward} and Oh, {Young Mi} and Wolfgang Pita-Thomas and Valeria Cavalli",

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Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α

Abstract

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