Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
Cell Rep. 2022 Feb 22;38(8):110407. doi: 10.1016/j.celrep.2022.110407.
Placenta hyperplasia is commonly observed in cloned animals and is believed to impede the proper development of cloned embryos. However, the mechanism underlying this phenomenon is largely unknown. Here, we show that placenta hyperplasia of cloned mouse embryos occurs in both middle and late gestation. Interestingly, restoring paternal-specific expression of an amino acid transporter Slc38a4, which loses maternal H3K27me3-dependent imprinting and becomes biallelically expressed in cloned placentae, rescues the overgrowth of cloned placentae at late gestation. Molecular analyses reveal that loss of Slc38a4 imprinting leads to over-activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in cloned placentae, which is likely due to the increased amino acids transport by SLC38A4. Collectively, our study not only reveals loss of Slc38a4 imprinting is responsible for overgrowth of cloned placentae at late gestation but also suggests the underlying mechanism involves increased amino acid transport and over-activation of mTORC1.
胎盘增生在克隆动物中很常见，被认为会阻碍克隆胚胎的正常发育。然而，这种现象的机制在很大程度上尚不清楚。在这里，我们表明克隆小鼠胚胎的胎盘增生发生在妊娠中期和晚期。有趣的是，恢复氨基酸转运蛋白 Slc38a4 的父本特异性表达，该基因在克隆胎盘组织中失去了母本 H3K27me3 依赖性印迹，成为双等位基因表达，可挽救克隆胎盘在妊娠晚期的过度生长。分子分析表明，Slc38a4 印迹的丧失导致克隆胎盘中雷帕霉素复合物 1 (mTORC1) 信号通路的过度激活，这可能是由于 SLC38A4 增加了氨基酸的转运。总的来说，我们的研究不仅揭示了 Slc38a4 印迹的丧失是导致克隆胎盘在妊娠晚期过度生长的原因，还表明其潜在机制涉及增加氨基酸转运和 mTORC1 的过度激活。
