The Rodent-Specific MicroRNA Cluster within the Sfmbt2 Gene Is Imprinted and Essential for Placental Development

Abstract

Summary: MicroRNAs (miRNAs) represent small noncoding RNAs that are involved in physiological and developmental processes by posttranscriptionally inhibiting gene expression. One of the largest miRNA clusters in mice is located in intron 10 of the Sfmbt2 gene, containing 72 miRNA precursor sequences. In this study, we generated mice lacking the entire Sfmbt2 miRNA cluster to elucidate its functions during development. The Sfmbt2 miRNAs were expressed predominantly from the paternal allele in the placenta, as is the host Sfmbt2 gene. Loss of the paternal allele resulted in severely impaired development of the placenta, especially the spongiotrophoblast layer, and frequent lethality or defects of fetuses. The predicted target sequences of the miRNAs and gene expression analysis defined at least nine putative target genes, which function as tumor suppressors or apoptosis inducers. Our study has provided experimental evidence for the indispensable roles of placental miRNAs in trophoblast proliferation and thus fetal development. : Inoue et al. use 53-kb knockout mice to uncover the function of the miRNAs that comprise the largest cluster in mice. These miRNAs promote spongiotrophoblast cell proliferation by suppressing target genes with cell-proliferation-regulator or tumor-repressor functions, in cooperation with the host Sfmbt2 gene under the same imprinted placental expression control. Keywords: microRNA, imprinted gene, placenta, CRISPR/Cas9, miRNA gene cluster, spongiotrophoblast layer