A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca²⁺Release During Axonal Specification

Abstract

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.