Deficiency of autotaxin/lysophospholipase D results in head cavity formation in mouse embryos through the LPA receptor-Rho-ROCK pathway.
Autotaxin, encoded by the Enpp2 gene, generates lysophosphatidic acid (LPA) extracellularly, eliciting various cellular responses through specific LPA receptors. Previous studies have revealed that Enpp2(-/-) mice die at E9.5 owing to angiogenic defects in the yolk sac. Moreover, Enpp2(-/-) embryos show growth retardation, allantois malformation, no axial turning, and head cavity formation. We have also demonstrated that lysosome biogenesis is impaired in yolk sac visceral endoderm cells of Enpp2(-/-) embryos as a result of the downregulation of the Rho-ROCK (Rho-associated coiled-coil containing protein kinase)-LIM kinase pathway. In this study, we examine what signaling defect(s) is responsible for head cavity formation and yolk sac angiogenic defects. By using a whole embryo culture system, we show that 10 μM Ki16425, an antagonist for the LPA receptors, induces head cavity formation and yolk sac angiogenic defects in wild-type embryos. Moreover, 1 μM Ki16425 induces both phenotypes in Enpp2 heterozygous embryos at significantly higher incidence than in wild-type embryos, suggesting an interaction between autotaxin and LPA receptor signaling. Furthermore, we show that inhibition of the Rho-ROCK pathway induces head cavity formation, whereas multiple pathways are involved in yolk sac angiogenic defects. These results reveal the signal transduction defects that underlie the abnormalities in Enpp2(-/-) embryos.
Koike
Seiichi
S
Department of Molecular Neurobiology, Graduate School of Comprehensive Human Sciences, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
Keino-Masu
Kazuko
K
Masu
Masayuki
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000378:metabolism; D006257:Head / Q000002:abnormalities*; D051379:Mice; D008817:Mice, Mutant Strains; D009097:Multienzyme Complexes / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics; D043264:Phosphodiesterase I / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012234:Rho Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015017:Yolk Sac / Q000002:abnormalities / Q000098:blood supply; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099189:Lysophospholipase D
D000199:Actins; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D012234:Rho Factor; D054460:rho-Associated Kinases; D000099189:Lysophospholipase D