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

James J.A. Contos, Isao Ishii, Nobuyuki Fukushima, Marcy A. Kingsbury, Xiaoqin Ye, Shuji Kawamura, Joan Heller Brown, Jerold Chun

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265 Citations (Scopus)

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/lpA1/Edg-2/Gpcr26, lpa2/lpA2/Edg-4, and lpa3/lpA3/ 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.

Original languageEnglish
Pages (from-to)6921-6929
Number of pages9
JournalMolecular and cellular biology
Volume22
Issue number19
DOIs
Publication statusPublished - 2002 Oct

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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