title: A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca2+ Release During Axonal Specification.
abstract: Physiological levels of ROS support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shape neurons remain unknown. Ca2+, a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca2+release from the endoplasmic reticulum, mediated by both the IP3R1 and ryanodine receptor (RyR) channels, requires physiological ROS levels that are mainly sustained by the NADPH oxidase (NOX) complex. In this work, we explore the contribution of the link between NOX and RyR-mediated Ca2+release toward axonal specification of rat hippocampal neurons. Using genetic approaches, we find that NOX activation promotes both axonal development and Rac1 activation through a RyR-mediated mechanism, which in turn activates NOX through Rac1, one of the NOX subunits. Collectively, these data suggest a feedforward mechanism that integrates both NOX activity and RyR-mediated Ca2+release to support cellular mechanisms involved in axon development.
  
  
  
  High levels of ROS are frequently associated with oxidative stress and disease. In contrast, physiological levels of ROS, mainly sustained by the NADPH oxidase (NOX) complex, promote neuronal development and axonal growth. However, the mechanisms by which ROS shape neurons have not been described. Our work suggests that NOX-derived ROS promote axonal growth by regulating Rac1 activity, a molecular determinant of axonal growth, through a ryanodine receptor (RyR)-mediated Ca2+release mechanism. In addition, Rac1, one of the NOX subunits, was activated after RyR-mediated Ca2+release, suggesting a feedforward mechanism between NOX and RyR. Collectively, our data suggest a novel mechanism that is instrumental in sustaining physiological levels of ROS required for axonal growth of hippocampal neurons.
authors: Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile.|Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
authors: Carlos
authors: 0000-0001-5328-4180
authors: C
authors: Wilson
authors: Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile.|Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
authors: Ernesto
authors: 0000-0002-2938-3944
authors: E
authors: Muñoz-Palma
authors: Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile.|Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
authors: Daniel R
authors: 0000-0002-1761-1217
authors: DR
authors: Henríquez
authors: Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, W12 ONN London, United Kingdom.
authors: Ilaria
authors: I
authors: Palmisano
authors: Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile.
authors: M Tulio
authors: MT
authors: Núñez
authors: Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, W12 ONN London, United Kingdom.|Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany, and.
authors: Simone
authors: S
authors: Di Giovanni
authors: Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile, chrgonza@uchile.cl.|Geroscience Center for Brain Health and Metabolism, Santiago, Chile.|The Buck Institute for Research on Aging, Novato, California 94945.
authors: Christian
authors: C
authors: González-Billault
mesh_terms: D000818:Animals; D000071437:Axon Guidance / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006624:Hippocampus / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D019255:NADPH Oxidases; D002118:Calcium
keywords: NADPH oxidase; actin cytoskeleton; axon development; calcium signaling; neuronal differentiation; reactive oxygen species