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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)

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Overview

authors

  • Contos, J. J. A.
  • Ishii, I.
  • Fukushima, N.
  • Kingsbury, M. A.
  • Ye, X. Q.
  • Kawamura, S.
  • Brown, J. H.
  • Chun, Jerold

publication date

  • October 2002

journal

  • Molecular and Cellular Biology  Journal

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.

subject areas

  • Adenylyl Cyclases
  • Animals
  • Calcium
  • Cell Division
  • Cells, Cultured
  • Cerebral Cortex
  • Crosses, Genetic
  • Enzyme Activation
  • Female
  • Fibroblasts
  • Gene Targeting
  • Hematoma
  • Homozygote
  • Lysophospholipids
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophosphatidic Acid
  • Signal Transduction
  • Stress Fibers
  • Type C Phospholipases
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Identity

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/mcb.22.19.6921-6929.2002

PubMed ID

  • 12215548
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Additional Document Info

start page

  • 6921

end page

  • 6929

volume

  • 22

issue

  • 19

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