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Molecular and Cellular Biology, July 2006, p. 5015-5022, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02419-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Autotaxin, a Secreted Lysophospholipase D, Is Essential for Blood Vessel Formation during Development

Laurens A. van Meeteren,1 Paula Ruurs,1 Catelijne Stortelers,1 Peter Bouwman,2 Marga A. van Rooijen,3 Jean Philippe Pradère,4 Trevor R. Pettit,5 Michael J. O. Wakelam,5 Jean Sébastien Saulnier-Blache,4 Christine L. Mummery,3 Wouter H. Moolenaar,1* and Jos Jonkers2

Division of Cellular Biochemistry and Center for Biomedical Genetics,1 Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands,2 Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands,3 INSERM U586, Unité de Recherches sur les Obésités, 31432 Toulouse, France,4 CRUK Institute for Cancer Studies, Birmingham University, Birmingham B15 2TT, United Kingdom5

Received 20 December 2005/ Returned for modification 13 March 2006/ Accepted 20 April 2006

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 G{alpha}13 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 G{alpha}13.

* Corresponding author. Mailing address: Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31-20-512-1971. Fax: 31-20-512-1989. E-mail: w.moolenaar{at}nki.nl.

Molecular and Cellular Biology, July 2006, p. 5015-5022, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02419-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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