LPA₂ promotes neuronal differentiation and neurite formation in neocortical development

Lysophosphatidic acid (LPA) is a bioactive lipid that activates the G protein-coupled receptors, LPA_1-6, which are associated with a wide number of cellular responses including proliferation, migration, differentiation, and survival. Although LPA_1-6 are expressed in the developing brain, their functions in brain development are not fully understood. In the present study, we analyzed the temporal expression pattern of LPA receptors (LPARs) during neocortical development and found that LPA₂ is highly expressed in neural stem/progenitor cells (NS/PCs) in the embryonic neocortex. LPA₂ activation on cultured NS/PCs using GRI977143, a selective LPA₂ agonist, promoted neuronal differentiation. LPA₂-induced neuronal expansion was inhibited by FR180204, an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, suggesting that LPA₂ promotes neuronal differentiation via Erk1/2 signaling. In addition, LPA₂ activation promotes neurite elongation and branch formation. These results suggest that LPA₂ is a critical regulator of neuronal differentiation and development.