Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.
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.
van Meeteren
Laurens A
LA
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Ruurs
Paula
P
Stortelers
Catelijne
C
Bouwman
Peter
P
van Rooijen
Marga A
MA
Pradère
Jean Philippe
JP
Pettit
Trevor R
TR
Wakelam
Michael J O
MJ
Saulnier-Blache
Jean Sébastien
JS
Mummery
Christine L
CL
Moolenaar
Wouter H
WH
Jonkers
Jos
J
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
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