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Molecular and Cellular Biology, October 2002, p. 6921-6929, Vol. 22, No. 19
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.19.6921-6929.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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,1 Isao Ishii,1,2 Nobuyuki Fukushima,1,3 Marcy A. Kingsbury,1 Xiaoqin Ye,1 Shuji Kawamura,1 Joan Heller Brown,1 and Jerold Chun1*

Department of Pharmacology, Neurosciences and Biomedical Sciences Programs, School of Medicine, University of California, San Diego, La Jolla, California 92093-0636,1 Department of Molecular Genetics, National Institute of Neuroscience, Ogawahigashi 4-1-1, Kodaira, Tokyo 187-8502,2 Department of Biochemistry, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan3

Received 28 January 2002/ Returned for modification 5 March 2002/ Accepted 9 July 2002

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.

* Corresponding author. Mailing address: Merck Research Laboratories, San Diego, 3535 General Atomics Court, San Diego, CA 92121. Phone: (858) 202-5232. Fax: (858) 202-5813. E-mail: jerold_chun{at}merck.com.

Molecular and Cellular Biology, October 2002, p. 6921-6929, Vol. 22, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.19.6921-6929.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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