ABSTRACT
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.
A reduced susceptibility to chemoconvulsant stimulation in adenylyl cyclase 8 knockout mice
