Affiliation:
1. Department of Pharmacology, Neurosciences and Biomedical Sciences Programs, School of Medicine, University of California, San Diego, La Jolla, California 92093-0636
2. Department of Molecular Genetics, National Institute of Neuroscience, Ogawahigashi 4-1-1, Kodaira, Tokyo 187-8502
3. Department of Biochemistry, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan
Abstract
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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
290 articles.
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