Abstract
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-Δ12,14-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.
Highlights
Neuritogenesis is an early event in the differentiation of neural progenitor cells into neurons and enables neurons to develop axons and dendrites with which they connect to other cells and receive and transmit electrical signals [1]
We found that exogenously applied prostaglandin D2 (PGD2) was converted to 15d-prostaglandin J2 (PGJ2) and subsequently induced neurite outgrowth, which was mediated by peroxisome proliferator-activated receptor γ (PPARγ) but not by D-prostanoid receptor (DP) in motor neuron-like cells
The maximal effect of PGD2 was observed at 15 μM, with an increase of up to approximately 30%
Summary
Neuritogenesis is an early event in the differentiation of neural progenitor cells into neurons and enables neurons to develop axons and dendrites with which they connect to other cells and receive and transmit electrical signals [1]. Understanding the mechanism involved in neuritogenesis and differentiation of spinal motor neurons could pave the way for the development of regenerative therapies for motor neuron diseases. NSC-34 cells are produced by the fusion of mouse neuroblastoma cells with motor neuron-enriched mouse spinal cord cells [4]. Differentiated NSC-34 cells induced by serum deprivation and additional treatment with all-trans retinoic acid exhibit the unique morphological and physiological characteristics of motor neurons, including neurite outgrowth, expression of motor neuron-specific marker proteins HB9 and Islet-1, and acetylcholine synthesis and storage [5,6]. Undifferentiated NSC-34 cells are widely used as motor neuron progenitor cells in the search for small molecular compounds that induce motor neuron differentiation [7,8,9,10]
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