Lysophosphatidic acid induces neurite branch formation through LPA3

Although neurite branching is crucial for neuronal network formation after birth, its underlying mechanisms remain unclear. Here, we demonstrate that lysophosphatidic acid (LPA) stimulates neurite branching through a novel signaling pathway. Treatment of neuronal cell lines with LPA resulted in neurite branch formation when LPA3 receptor was introduced. The effects of LPA were blocked by inhibition of Gq signaling. Furthermore, expression of inhibitory mutants of the small GTPase Rnd2/Rho7 or an Rnd2 effector rapostlin abolished LPA3-mediated neurite branching. The LPA3 agonist 2(S)-OMPT or LPA also induced axonal branch formation in hippocampal neurons, which was blocked by Gq and Rnd2 pathway inhibition or LPA3 knockdown. These findings suggest that the novel signaling pathway involving LPA3, Gq, and Rnd2 may play an important role in neuronal network formation.