Intracellular calcium ions (Ca2+) have an essential role in the regulation of neurite outgrowth. but how outgrowth is controlled remains largely unknown. In this study, we examined how the mechanisms of neurite outgrowth change during development in chick and mouse dorsal root ganglion neurons. 2APB, a potent inhibitor of inositol 1,45-trisphosphate (IP3) receptors (IP3R), inhibited neurite outgrowth at early developmental stages, but not at later stages. In contrast, pharmacological inhibition with Ni2+, Cd2+, or dantrolene revealed chat ryanodine receptor (RyR)-mediated Ca2+-induced Ca2+ release (CICR) was involved in neurite outgrowth at later stage, but not at early stages. The distribution of IP3R and RyR in growth cones also changed during development. Furthermore, pharmacological inhibition of the Ca2+-calmodulin-dependent phosphatase calcineurin with FK506 reduced neurite outgrowth only at early stages. These data Suggest that the calcium signaling that regulates neurite Outgrowth may change during development from an IP3R-mediated pathway to a RyR-mediated pathway. (C) 2008 Elsevier Inc. All rights reserved.