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.
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Yongcheol
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Shin
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Eric Edward
authors.initials: EE
authors.lastname: Ewan
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Oh
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Pita-Thomas
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: cavalli@pcg.wustl.edu.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cavalli
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D066298:In Vitro Techniques; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics*; D009469:Neuromuscular Junction; D059348:Peripheral Nerve Injuries / Q000235:genetics* / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse