Severe damage on placental fetal capillary network causes mid to late fetal lethality and reduction of placental size in Peg11/Rtl1 KO mice [day 10.5]

Paternally expressed 11/Retrotransposon-like 1 (Peg11/Rtl1) knockout (KO) mice exhibited mid to late fetal lethality or late fetal growth retardation associated with frequent neonatal lethality. The lethal phenotype was largely dependent on genetic background and became more severe with each succeeding generation in the course of backcross experiments to C57BL/6 (B6). We previously suggested these lethal and growth phenotypes were due to severe defects in placental fetal capillaries in labyrinth layer. In this study, we reexamined KO fetuses exhibiting mid fetal lethality with internal bleeding. Importantly, basal region of fetal capillary network was specially damaged, therefore, also leading to poor expansion of the labyrinth layer and placental size reduction in later stage. Apparent up-regulation of Guanine nucleotide binding protein, alpha 2 (Gnai2) and decrement of Transmembrane protein 100 (Tmem100), Mesenchyme homeobox 2 (Meox2) and Lymphatic vessel hyaluronan Receptor 1 (LYVE1) expression were observed in earlier stage of placentas even before apparent morphological changes occurred, suggesting that these genes are involved in the maintenance of fetal capillaries associated with Peg11/Rtl1 in development. Gene expression profiles of WT and Peg11/Rtl1 KO placentas at day 10.5 were analyzed to identify genes involved in the maintenance of fetal capillary endothelial cells during earlier stage of the placenta.父本表达11/反转录转座子样1（Peg11/Rtl1）基因敲除（KO）小鼠表现出中晚期胎儿致死或晚期胎儿生长迟缓，并伴随频发的新生鼠致死现象。该致死表型在很大程度上依赖于遗传背景，且在回交至C57BL/6（B6）品系的实验中，随着后续世代的延续愈发严重。本研究团队此前曾提出，此类致死与生长表型源于胎盘迷路层的胎儿毛细血管存在严重缺陷。本研究重新分析了出现宫内出血且处于中期胎儿致死阶段的基因敲除胎鼠，结果显示胎儿毛细血管网络的基底区域出现特异性损伤，进而导致迷路层扩张不良以及后期胎盘体积缩小。在胎盘发育早期、甚至出现明显形态学变化之前，即可观察到鸟苷酸结合蛋白α亚基2（Gnai2）的表达显著上调，以及跨膜蛋白100（Tmem100）、间充质同源框2（Meox2）与淋巴管透明质酸受体1（LYVE1）的表达显著下调。上述结果提示，这些基因参与了发育过程中与Peg11/Rtl1相关的胎儿毛细血管维持功能。本研究对妊娠第10.5天的野生型（WT）与Peg11/Rtl1基因敲除胎盘开展基因表达谱分析，以筛选胎盘发育早期参与维持胎儿毛细血管内皮细胞功能的相关基因。