Genetics and cell biology of lysophosphatidic acid receptor-mediated signaling during cortical neurogenesis.

Lysophosphatidic acid (LPA) is a small lysophospholipid that signals through G-protein coupled receptors (GPCRs) to mediate diverse cellular responses. Two LPA receptors, LPA(1) and LPA(2), show gene expression profiles in mouse embryonic cerebral cortex, suggesting roles for LPA signaling in cerebral cortical development. Here, we review loss-of-function and gain-of-function models that have been used to examine LPA signaling. Genetic deletion of lpa(1) or both lpa(1) and lpa(2) in mice results in 50-65% neonatal lethality, but not obvious cortical phenotypes in survivors, suggesting that compensatory signaling systems exist for regulating cortical development. A gain-of-function model, approached by increasing receptor activation through exogenous delivery of LPA, shows that LPA signaling regulates cerebral cortical growth and anatomy by affecting proliferation, differentiation and cell survival during embryonic development.