Abstract
Autotaxin (ATX) is a secretory protein, which converts lysophospholipids to lysophosphatidic acid (LPA), and is essential for embryonic vascular formation. ATX is abundantly detected in various biological fluids and its level is elevated in some pathophysiological conditions. However, the roles of elevated ATX levels remain to be elucidated. In this study, we generated conditional transgenic (Tg) mice overexpressing ATX and examined the effects of excess LPA signalling. We found that ATX overexpression in the embryonic period caused severe vascular defects and was lethal around E9.5. ATX was conditionally overexpressed in the neonatal period using the Cre/loxP system, which resulted in a marked increase in the plasma LPA level. This resulted in retinal vascular defects including abnormal vascular plexus and increased vascular regression. Our findings indicate that the ATX level must be carefully regulated to ensure coordinated vascular formation
Highlights
Autotaxin (ATX) is a motogen-like phosphodiesterase that was originally isolated from conditioned medium of human melanoma cells [1]
lysophosphatidic acid (LPA) is a lipid mediator with diverse biological functions in vitro and in vivo, most of which are mediated by G protein-coupled receptors (GPCRs) specific to LPA (LPA1–6) [4,5,6]
ATX catalytic activity must be responsible for these phenotypes because mutated ATX knock-in embryos, in which a single amino acid responsible for the catalytic activity of ATX was modified, are embryonic lethal [11]
Summary
Autotaxin (ATX) is a motogen-like phosphodiesterase that was originally isolated from conditioned medium of human melanoma cells [1]. We found that ATX overexpression in the embryonic period caused severe vascular defects and was lethal around E9.5. ATX was conditionally overexpressed in the neonatal period using the Cre/loxP system, which resulted in a marked increase in the plasma LPA level.
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