title: Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.
abstract: Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that promotes cell migration, metastasis, and angiogenesis. ATX generates lysophosphatidic acid (LPA), a lipid mitogen and motility factor that acts on several G protein-coupled receptors. Here we report that ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Galpha13 knockout phenotype. Furthermore, at E8.5, ATX-deficient embryos showed allantois malformation, neural tube defects, and asymmetric headfolds. The onset of these abnormalities coincided with increased expression of ATX and LPA receptors in normal embryos. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. Our results reveal a critical role for ATX in vascular development, indicate that ATX is the major LPA-producing enzyme in vivo, and suggest that the vascular defects in ATX-deficient embryos may be explained by loss of LPA signaling through Galpha13.
authors.affiliation: Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Laurens A
authors.initials: LA
authors.lastname: van Meeteren
authors.forename: Paula
authors.initials: P
authors.lastname: Ruurs
authors.forename: Catelijne
authors.initials: C
authors.lastname: Stortelers
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: Marga A
authors.initials: MA
authors.lastname: van Rooijen
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Pradère
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Pettit
authors.forename: Michael J O
authors.initials: MJ
authors.lastname: Wakelam
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities* / Q000201:enzymology; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000098:blood supply / Q000201:enzymology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D005804:Genes, Lethal; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D044365:GTP-Binding Protein alpha Subunits, G12-G13; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid