The Molecular Mechanisms Underlying Prostaglandin D₂-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 E₂ 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 D₂ (PGD₂) on neuritogenesis in NSC-34 cells. Exposure to PGD₂ 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 PGD₂ (a DP2 agonist) had no effect on neurite outgrowth. Enzyme-linked immunosorbent assay demonstrated that PGD₂ was converted to 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) under cell-free conditions. Exogenously applied 15d-PGJ₂ mimicked the effect of PGD₂ on neurite outgrowth. GW9662, a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist, suppressed PGD₂-induced neurite outgrowth. Moreover, PGD₂ and 15d-PGJ₂ 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 PGD₂ induces neuritogenesis in NSC-34 cells and that PGD₂-induced neurite outgrowth was mediated by the activation of PPARγ through the metabolite 15d-PGJ₂.