Deficiency of autotaxin/lysophospholipase D results in head cavity formation in mouse embryos through the LPA receptor-Rho-ROCK pathway桝, 和子桝, 正幸Koike, SeiichiKeino-Masu, KazukoMasu, Masayuki© 2010 Elsevier Inc.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.Elsevier Inc.2010-09engjournal articlehttp://hdl.handle.net/2241/106640https://tsukuba.repo.nii.ac.jp/records/204922069223510.1016/j.bbrc.2010.08.0080006-291XAA00564395Biochemical and biophysical research communications40016671https://tsukuba.repo.nii.ac.jp/record/20492/files/BBRC_400-1.pdfapplication/pdf719.0 kB2013-12-24