title: Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2).
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 lpa(1)/lp(A1)/Edg-2/Gpcr26, lpa(2)/lp(A2)/Edg-4, and lpa(3)/lp(A3)/Edg-7 mediate the cellular effects of LPA. We have previously shown that deletion of lpa(1) 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 lpa(2) in mice. Homozygous knockout (lpa(2)((-/-))) mice were born at the expected frequency and displayed no obvious phenotypic abnormalities. Intercrosses allowed generation of lpa(1)((-/-)) lpa(2)((-/-)) double knockout mice, which displayed no additional phenotypic abnormalities relative to lpa(1)((-/-)) mice except for an increased incidence of perinatal frontal hematoma. Histological analyses of lpa(1)((-/-)) lpa(2)((-/-)) embryonic cerebral cortices did not reveal obvious differences in the proliferating cell population. However, many LPA-induced responses, including phospholipase C activation, Ca(2+) mobilization, adenylyl cyclase activation, proliferation, JNK activation, Akt activation, and stress fiber formation, were absent or severely reduced in embryonic fibroblasts derived from lpa(1)((-/-)) lpa(2)((-/-)) mice. Except for adenylyl cyclase activation [which was nearly abolished in lpa(1)((-/-)) fibroblasts], these responses were only partially affected in lpa(1)((-/-)) and lpa(2)((-/-)) fibroblasts. Thus, although LPA(2) is not essential for normal mouse development, it does act redundantly with LPA(1) to mediate most LPA responses in fibroblasts.
authors.affiliation: Department of Pharmacology, Neurosciences and Biomedical Sciences Programs, School of Medicine, University of California, San Diego, La Jolla 92093-0636, USA.
authors.forename: James J A
authors.initials: JJ
authors.lastname: Contos
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fukushima
authors.forename: Marcy A
authors.initials: MA
authors.lastname: Kingsbury
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Ye
authors.forename: Shuji
authors.initials: S
authors.lastname: Kawamura
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D003433:Crosses, Genetic; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018390:Gene Targeting; D006406:Hematoma / Q000235:genetics; D006720:Homozygote; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D022502:Stress Fibers / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D002118:Calcium