Laboratory of Biochemistry and Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
Department of Cellular and Molecular Pharmacology, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan.
Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2200582119. doi: 10.1073/pnas.2200582119. Epub 2022 Apr 27.
The P4-ATPases ATP11A and ATP11C function as flippases at the plasma membrane to translocate phosphatidylserine from the outer to the inner leaflet. We herein demonstrated that Atp11a-deficient mouse embryos died at approximately E14.5 with thin-walled heart ventricles. However, the cardiomyocyte- or epiblast-specific Atp11a deletion did not affect mouse development or mortality. ATP11C may have compensated for the function of ATP11A in most of the cell types in the embryo. On the other hand, Atp11a, but not Atp11c, was expressed in the mouse placenta, and the Atp11a-null mutation caused poor development of the labyrinthine layer with an increased number of TUNEL-positive foci. Immunohistochemistry and electron microscopy revealed a disorganized labyrinthine layer with unfused trophoblasts in the Atp11a-null placenta. Human placenta-derived choriocarcinoma BeWo cells expressed the ATP11A and ATP11C genes. A lack of ATP11A and ATP11C eliminated the ability of BeWo cells to flip phosphatidylserine and fuse when treated with forskolin. These results indicate that flippases at the plasma membrane play an important role in the formation of syncytiotrophoblasts in placental development.
P4-ATPases ATP11A 和 ATP11C 作为翻转酶在质膜上发挥作用，将磷脂酰丝氨酸从外叶层转运到内叶层。本文证明，Atp11a 缺陷型小鼠胚胎在大约 E14.5 时死亡，心室壁薄。然而，心肌细胞或上胚层特异性的 Atp11a 缺失并不影响小鼠的发育或死亡率。ATP11C 可能在胚胎的大多数细胞类型中补偿了 ATP11A 的功能。另一方面，Atp11a 而不是 Atp11c 在小鼠胎盘中有表达，并且 Atp11a 缺失突变导致绒毛膜板层发育不良，TUNEL 阳性焦点数量增加。免疫组织化学和电子显微镜显示，Atp11a 缺失胎盘的绒毛膜板层排列紊乱，滋养层未融合。人胎盘来源的绒毛膜癌细胞系 BeWo 细胞表达 ATP11A 和 ATP11C 基因。缺乏 ATP11A 和 ATP11C 消除了 BeWo 细胞在 forskolin 处理时翻转磷脂酰丝氨酸和融合的能力。这些结果表明，质膜上的翻转酶在胎盘发育中合胞滋养层的形成中发挥重要作用。
