Characterization of lpa₂ (Edg4) and lpa₁/lpa₂ (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: Signaling deficits without obvious phenotypic abnormality attributable to lpa₂

Lysophosphatidic acid (LPA), a bioactive lipid produced by several cell types including postmitotic neurons and activated platelets, is thought to be involved in various biological processes, including brain development. Three cognate G protein-coupled receptors encoded by lpa₁/lp_A1/Edg-2/Gpcr26, lpa₂/lp_A2/Edg-4, and lpa₃/lp_A3/ Edg-7 mediate the cellular effects of LPA. We have previously shown that deletion of lpa₁ in mice results in craniofacial dysmorphism, semilethality due to defective suckling behavior, and generation of a small fraction of pups with frontal hematoma. To further investigate the role of these receptors and LPA signaling in the organism, we deleted lpa₂ in mice. Homozygous knockout (lpa₂^(-/-)) mice were born at the expected frequency and displayed no obvious phenotypic abnormalities. Intercrosses allowed generation of lpa₁^(-/-) lpa₂^(-/-) double knockout mice, which displayed no additional phenotypic abnormalities relative to lpa₁^(-/-) mice except for an increased incidence of perinatal frontal hematoma. Histological analyses of lpa₁^(-/-) lpa₂^(-/-) embryonic cerebral cortices did not reveal obvious differences in the proliferating cell population. However, many LPA-induced responses, including phospholipase C activation, Ca²⁺ mobilization, adenylyl cyclase activation, proliferation, JNK activation, Akt activation, and stress fiber formation, were absent or severely reduced in embryonic fibroblasts derived from lpa₁^(-/-) lpa₂^(-/-) mice. Except for adenylyl cyclase activation [which was nearly abolished in lpa₁^(-/-) fibroblasts], these responses were only partially affected in lpa₁^(-/-) and lpa₂^(-/-) fibroblasts. Thus, although LPA₂ is not essential for normal mouse development, it does act redundantly with LPA₁ to mediate most LPA responses in fibroblasts.