Overexpression of autotaxin, a lysophosphatidic acid-producing enzyme, enhances cardia bifida induced by hypo-sphingosine-1-phosphate signaling in zebrafish embryo.
Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are second-generation lysophospholipid mediators that exert multiple biological functions through their own cognate receptors. They are both present in the blood stream, activate receptors with similar structures (endothelial differentiation gene receptors), have similar roles in the vasculature and are vasoactive. However, it is unclear whether these lysophospholipid mediators cross-talk downstream of each receptor. Here, we provide in vivo evidence that LPA signaling counteracted S1P signaling. When autotaxin (Atx), an LPA-producing enzyme, was overexpressed in zebrafish embryos by injecting atx mRNA, the embryos showed cardia bifida, a phenotype induced by down-regulation of S1P signaling. A similar cardiac phenotype was not induced when catalytically inactive Atx was introduced. The cardiac phenotype was synergistically enhanced when antisense morpholino oligonucleotides (MO) against S1P receptor (s1pr2/mil) or S1P transporter (spns2) was introduced together with atx mRNA. The Atx-induced cardia bifida was prominently suppressed when embryos were treated with an lpar1 receptor antagonist, Ki16425, or with MO against lpar1. These results provide the first in vivo evidence of cross-talk between LPA and S1P signaling.
Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; Laboratory of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; Presto, JST, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan; Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan; Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Laboratory for Cardiovascular Molecular Dynamics, Riken Quantitative Biology Center, Furuedai 6-2-3, Suita Osaka 565-0874, Japan; and CREST, JST, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
Keita
K
Nakanaga
Kotaro
K
Hama
Kuniyuki
K
Kano
Takanao
T
Sato
Hiroshi
H
Yukiura
Asuka
A
Inoue
Daisuke
D
Saigusa
Hidetoshi
H
Tokuyama
Yoshihisa
Y
Tomioka
Hiroshi
H
Nishina
Atsuo
A
Kawahara
Junken
J
Aoki
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000002:abnormalities* / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000378:metabolism*; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D000099189:Lysophospholipase D
D007555:Isoxazoles; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D011422:Propionates; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D013110:Sphingosine; D000099189:Lysophospholipase D; C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; C060506:sphingosine 1-phosphate; C032881:lysophosphatidic acid
autotoxin; cardia bifida; lysophosphatidic acid; sphingosine-1-phosphate; zebrafish