The eutherian-specific miR-290/miR-371 cluster modulates placental growth and maternal-fetal transport

A family of vertebrate-specific microRNAs called the ESCC microRNAs regulates proliferation and differentiation of embryonic stem cells. The ESCC microRNAs arise from two genetic loci in mammals, the miR-290/miR-371 and miR-302 loci. While the miR-302 locus is found broadly among vertebrates, the miR-290/miR-371 locus is unique to eutherian species, suggesting a role in placental development. Here, we evaluate that role. A knockin reporter for the mouse miR-290 gene is expressed throughout the embryo until gastrulation, at which time it becomes specifically expressed in extraembryonic tissues and the germline. In the placenta, expression is limited to the trophoblast lineage, where it remains highly expressed until birth. Deletion of the miR-290 gene results in reduced trophoblast progenitor cell proliferation and a reduced DNA content in endoreduplicating trophoblast giant cells. A reduction in placental size precedes a reduction in fetal size and prenatal death of most knockout embryos. The vascular labyrinth shows disorganization with thickening of the barrier between maternal and fetal blood associated with reduced diffusion of a radioactive tracer. Multiple mRNA targets of the cluster miRNAs are upregulated. Together, these data uncover a critical function for the miR-290 in the regulation of a network of genes required for normal placental development, suggesting a central role for this microRNA cluster in the evolution of eutherian species. mRNA expression in miR-290 knockout and wild-type placenta.一类被命名为ESCC微RNA（microRNA）的脊椎动物特异性微RNA家族，可调控胚胎干细胞的增殖与分化。ESCC微RNA在哺乳动物中源自两个基因座位：miR-290/miR-371座位与miR-302座位。其中miR-302座位在脊椎动物中广泛存在，而miR-290/miR-371座位仅为真兽类物种所特有，提示其在胎盘发育中发挥功能。本研究针对这一功能进行了评估。 小鼠miR-290基因的敲入报告基因在整个胚胎中均有表达，直至原肠胚形成阶段；此时其表达特异性局限于胚外组织与生殖系。在胎盘中，该基因的表达仅限定于滋养层细胞谱系，且该谱系中的表达水平直至分娩前始终维持较高水平。敲除miR-290基因会导致滋养层祖细胞增殖能力下降，同时使内复制型滋养层巨细胞的DNA含量降低。多数基因敲除胚胎的胎盘体积减小先于胎儿体积减小，并最终引发大部分胚胎产前死亡。胎盘血管迷路结构出现紊乱，母胎血液间的屏障增厚，同时伴随放射性示踪剂扩散速率降低。该微RNA簇的多个mRNA靶基因表达上调。 综上，本研究揭示了miR-290在调控正常胎盘发育所需基因网络中的关键功能，提示该微RNA簇在真兽类物种的演化中发挥核心作用。本数据集包含miR-290基因敲除型与野生型胎盘中的mRNA表达数据。