The LPA-LPA4 axis is required for establishment of bipolar morphology and radial migration of newborn cortical neurons

ABSTRACT Newborn neurons in the developing neocortex undergo radial migration, a process that is coupled with their precise passage from multipolar to bipolar shape. The cell-extrinsic signals that govern this transition are, however, poorly understood. Here, we find that lysophosphatidic acid (LPA) signaling contributes to the establishment of a bipolar shape in mouse migratory neurons through LPA receptor 4 (LPA4). LPA4 is robustly expressed in migratory neurons. LPA4-depleted neurons show impaired multipolar-to-bipolar transition and become arrested in their migration. Further, LPA4-mediated LPA signaling promotes formation of the pia-directed process in primary neurons overlaid on neocortical slices. In addition, LPA4 depletion is coupled with altered actin organization as well as with destabilization of the F-actin-binding protein filamin A (FlnA). Finally, overexpression of FlnA rescues the morphology and migration defects of LPA4-depleted neurons. Thus, the LPA-LPA4 axis regulates bipolar morphogenesis and radial migration of newborn cortical neurons via remodeling of the actin cytoskeleton. Summary: A knockdown study of lysophosphatidic acid receptor 4 in the developing mouse neocortex reveals that it regulates bipolar morphology and radial migration of newborn neurons through F-actin reorganization.

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