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. Ca 2, a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca 2 releasefromthe endoplasmic reticulum, mediated by boththe 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 Ca 2 release toward axonal specification of rat hippocampal neurons. Using genetic approaches, we find thatNOX activation promotes both axonal development and Rac1 activationthrough a RyR-mediatedmechanism,whichinturn activates NOX through Rac1, one of the NOX subunits. Collectively, these data suggest a feedforward mechanism that integrates both NOX activity and RyR-mediated Ca 2 release to support cellular mechanisms involved in axon development.