Role of RXR in neurite outgrowth induced by docosahexaenoic acid

We have previously demonstrated that docosahexaenoic acid (DHA) at low micromolar concentrations has a remarkable effect on morphological differentiation of hippocampal neurons by increasing the population of neurons with more branches and longer neurites. In this study, possible involvement of the retinoid X receptor (RXR) in the DHA-induced hippocampal neurite outgrowth was evaluated as DHA is an endogenous ligand for RXR. Immunocytochemical examination revealed that all RXR isoforms, RXR-α, -β1, -β2, and -γ, are expressed exclusively in neurons with distinctive intracellular distribution. The cell-based dual luciferase reporter assay indicated that DHA activates RXR-α at or above 10 μM but not at 1.5 μM where DHA induces neurite outgrowth. Arachidonic acid also activated RXR-α in a similar concentration range but with lower efficacy. Our results suggest that DHA-induced neurite outgrowth may not be mediated by direct activation of RXR-α, although involvement of other isoforms or DHA metabolites cannot be excluded.