The autotaxin-LPA axis promotes membrane trafficking and secretion in yolk sac visceral endoderm cells

Autotaxin, encoded by the Enpp2 gene, is an exoenzyme that produces lysophosphatidic acid, thereby regulating many biologic functions. We previously reported that Enpp2 mRNA was abundantly expressed in yolk sac visceral endoderm (VE) cells and that Enpp2(-/-) mice were lethal at embryonic day 9.5 owing to angiogenic defects in the yolk sac. Enpp2(-/-) mice showed lysosome fragmentation in VE cells and embryonic abnormalities including allantois malformation, neural tube defects, no axial turning, and head cavity formation. However, whether the defects in endocytic vesicle formation affect membrane trafficking in VE cells remained to be directly examined. In this study, we found that pinocytosis, transcytosis, and secretion of angiogenic factors such as vascular endothelial growth factor and transforming growth factor beta 1 were impaired in Enpp2(-/-) VE cells. Moreover, pharmacologic inhibition of membrane trafficking phenocopied the defects of Enpp2(-/-) mice. These findings demonstrate that Enpp2 promotes endocytosis and secretion of angiogenic factors in VE cells, thereby regulating angiogenesis/vasculogenesis and embryonic development.