Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) Lysophosphatidic Acid Receptor Knockout Mice: Signaling Deficits without Obvious Phenotypic Abnormality Attributable to lpa2
AUTOR(ES)
Contos, James J. A.
FONTE
American Society for Microbiology
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=134025Documentos Relacionados
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