Abstract
Lysophosphatidic acid (LPA) is a second-generation lysophospholipid mediator that exerts multiple biological functions through its own cognate receptors. LPA is produced by specific enzymatic reactions and activates receptors with similar structures (Edg receptors and P2Y receptors), which results in a variety of actions from embryonic blood vessel formation to development of cancer. LPA-related genes are highly conserved in vertebrates. In the zebrafish genome, three LPA-producing enzymes and nine LPA receptors are present. In vitro experiments have shown that LPA-related genes in zebrafish are conserved biochemically. LPA-related genes can be up- and downregulated by injecting morpholino antisense oligonucleotides (MOs) specific to LPA-related genes or mRNAs in zebrafish embryos. Such tools help to assess the biological function of these genes. For example, knockdown of the LPA-produced enzyme autotaxin (ATX) in zebrafish embryos resulted in malformation of embryonic blood vessel formation, which has also been observed in embryos from ATX-knockout mice. Simultaneous inactivation of multiple genes is possible by injecting more than one MO in zebrafish embryos, which makes it possible to identify the LPA receptors responsible for embryonic blood vessel formation. Gene functions can be also eliminated in zebrafish embryos by pharmacological tools such as enzyme inhibitors or receptor antagonists. Interestingly, overexpression of ATX in zebrafish embryos resulted in duplication of the heart (two-heart phenotype) and the phenotype was canceled by treating the embryos with LPA receptor antagonists. The zebrafish system is a powerful tool not only for identification of gene functions but also for development of drugs against enzymes and receptors.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- ATX:
-
Autotaxin
- Edg:
-
Endothelial differentiation gene
- hpf:
-
Hours post fertilization
- LPA:
-
Lysophosphatidic acid
- LPC:
-
Lysophosphatidylcholine
- MO:
-
Morpholino antisense oligonucleotide
- S1P:
-
Sphingosine-1-phosphate
References
Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J (2000) Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci U S A 97:13384–13389
Ye X et al (2005) LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435:104–108
Sumida H et al (2010) LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. Blood 116:5060–5070
Pasternack SM et al (2008) G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet 40:329–334
Tager AM et al (2008) The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14:45–54
Lin S et al (2009) The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer. Gastroenterology 136:1711–1720
Lin S, Lee SJ, Shim H, Chun J, Yun CC (2010) The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine. Am J Physiol Gastrointest Liver Physiol 299:G1128–G1138
Deng W et al (2002) Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis. Gastroenterology 123:206–216
Aoki J, Inoue A, Okudaira S (2008) Two pathways for lysophosphatidic acid production. Biochim Biophys Acta 1781:513–518
Tanaka M et al (2006) Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J Biol Chem 281:25822–25830
van Meeteren LA et al (2006) Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol 26:5015–5022
Kazantseva A et al (2006) Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH. Science 314:982–985
Inoue A et al (2011) LPA-producing enzyme PA-PLA(1)alpha regulates hair follicle development by modulating EGFR signalling. EMBO J 30:4248–4260
Brindley DN, Pilquil C (2009) Lipid phosphate phosphatases and signaling. J Lipid Res 50(suppl):S225–S230
Howe K et al (2013) The zebrafish reference genome sequence and its relationship to the human genome. Nature 496:498–503
Ellertsdottir E et al (2010) Vascular morphogenesis in the zebrafish embryo. Dev Biol 341:56–65
Corey DR, Abrams JM (2001) Morpholino antisense oligonucleotides: tools for investigating vertebrate development. Genome Biol 2: REVIEWS1015
Bedell VM et al (2012) In vivo genome editing using a high-efficiency TALEN system. Nature 491:114–118
Hwang WY et al (2013) Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat Biotechnol 31:227–229
Yukiura H et al (2011) Autotaxin regulates vascular development via multiple lysophosphatidic acid (LPA) receptors in zebrafish. J Biol Chem 286:43972–43983
Fotopoulou S et al (2010) ATX expression and LPA signalling are vital for the development of the nervous system. Dev Biol 339:451–464
Ruppel KM et al (2005) Essential role for Galpha13 in endothelial cells during embryonic development. Proc Natl Acad Sci U S A 102:8281–8286
Kamijo H et al (2011) Impaired vascular remodeling in the yolk sac of embryos deficient in ROCK-I and ROCK-II. Genes Cells 16:1012–1021
Ferry G et al (2007) Functional invalidation of the autotaxin gene by a single amino acid mutation in mouse is lethal. FEBS Lett 581:3572–3578
Yang AH, Ishii I, Chun J (2002) In vivo roles of lysophospholipid receptors revealed by gene targeting studies in mice. Biochim Biophys Acta 1582:197–203
Lin ME, Rivera RR, Chun J (2012) Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain. J Biol Chem 287:17608–17617
Lawson ND, Weinstein BM (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248:307–318
Yuelling LW, Waggener CT, Afshari FS, Lister JA, Fuss B (2012) Autotaxin/ENPP2 regulates oligodendrocyte differentiation in vivo in the developing zebrafish hindbrain. Glia 60:1605–1618
Lai SL et al (2012) Autotaxin/Lpar3 signaling regulates Kupffer’s vesicle formation and left-right asymmetry in zebrafish. Development 139:4439–4448
Nakanaga K et al (2014) Overexpression of autotaxin, a lysophosphatidic acid-producing enzyme, enhances cardia bifida induced by hypo-sphingosine-1-phosphate signaling in zebrafish embryo. J Biochem 155:235–241
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Japan
About this chapter
Cite this chapter
Aoki, J., Yukiura, H. (2015). Zebrafish as a Model Animal for Studying Lysophosphatidic Acid Signaling. In: Yokomizo, T., Murakami, M. (eds) Bioactive Lipid Mediators. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55669-5_14
Download citation
DOI: https://doi.org/10.1007/978-4-431-55669-5_14
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55668-8
Online ISBN: 978-4-431-55669-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)