The eutheria-specific miR-290 cluster modulates placental growth and maternal-fetal transport

A family of vertebrate-specific microRNAs called the ESCC microRNAs arises 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 eutheria (placental mammals), suggesting a role in placental development. Here, we evaluate that role. A knockin reporter for the mouse miR-290 cluster 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 cluster gene results in reduced trophoblast progenitor cell proliferation and a reduced DNA content in endoreduplicating trophoblast giant cells. The resulting placenta is reduced in size. In addition, the vascular labyrinth is disorganized with thickening of the maternal-fetal blood barrier and an associated reduction in diffusion of a radioactive tracer. Multiple mRNA targets of the cluster miRNAs are upregulated. Together, these data uncover a critical function for miR-290 cluster 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 placental mammals.