The Molecular Mechanisms Underlying Prostaglandin D(2)-Induced Neuritogenesis in Motor Neuron-Like NSC-34 Cells

Prostaglandins are a group of physiologically active lipid compounds derived from arachidonic acid. Our previous study has found that prostaglandin E(2) promotes neurite outgrowth in NSC-34 cells, which are a model for motor neuron development. However, the effects of other prostaglandins on neuronal differentiation are poorly understood. The present study investigated the effect of prostaglandin D(2) (PGD(2)) on neuritogenesis in NSC-34 cells. Exposure to PGD(2) resulted in increased percentages of neurite-bearing cells and neurite length. Although D-prostanoid receptor (DP) 1 and DP2 were dominantly expressed in the cells, BW245C (a DP1 agonist) and 15(R)-15-methyl PGD(2) (a DP2 agonist) had no effect on neurite outgrowth. Enzyme-linked immunosorbent assay demonstrated that PGD(2) was converted to 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) under cell-free conditions. Exogenously applied 15d-PGJ(2) mimicked the effect of PGD(2) on neurite outgrowth. GW9662, a peroxisome proliferator-activated receptor–gamma (PPARγ) antagonist, suppressed PGD(2)-induced neurite outgrowth. Moreover, PGD(2) and 15d-PGJ(2) increased the protein expression of Islet-1 (the earliest marker of developing motor neurons), and these increases were suppressed by co-treatment with GW9662. These results suggest that PGD(2) induces neuritogenesis in NSC-34 cells and that PGD(2)-induced neurite outgrowth was mediated by the activation of PPARγ through the metabolite 15d-PGJ(2).