van Meeteren Laurens A, Ruurs Paula, Stortelers Catelijne, Bouwman Peter, van Rooijen Marga A, Pradère Jean Philippe, Pettit Trevor R, Wakelam Michael J O, Saulnier-Blache Jean Sébastien, Mummery Christine L, Moolenaar Wouter H, Jonkers Jos
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Mol Cell Biol. 2006 Jul;26(13):5015-22. doi: 10.1128/MCB.02419-05.
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.
自分泌运动因子（ATX），即核苷酸焦磷酸酶 - 磷酸二酯酶2，是一种分泌型溶血磷脂酶D，可促进细胞迁移、转移和血管生成。ATX可生成溶血磷脂酸（LPA），一种作用于多种G蛋白偶联受体的脂质有丝分裂原和运动因子。在此我们报告，ATX缺陷型小鼠在胚胎第9.5天（E9.5）死亡，卵黄囊和胚胎中存在严重的血管缺陷，类似于Gα13基因敲除表型。此外，在E8.5时，ATX缺陷型胚胎出现尿囊畸形、神经管缺陷和不对称头褶。这些异常的出现与正常胚胎中ATX和LPA受体表达增加相一致。ATX杂合子小鼠看起来健康，但ATX活性和血浆LPA水平仅为正常的一半。我们的结果揭示了ATX在血管发育中的关键作用，表明ATX是体内主要的LPA产生酶，并提示ATX缺陷型胚胎中的血管缺陷可能是由于通过Gα13的LPA信号缺失所致。
