A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca super(2+) Release During Axonal Specification

Physiological levels of ROS support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shape neurons remain unknown. Ca super(2+), a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca super(2+) 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 Ca super(2+) 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 Ca super(2+) release to support cellular mechanisms involved in axon development.