RNA exosome ribonuclease DIS3 degrades Pou6f1 to promote mouse pre-implantation cell differentiation.

Mammalian development is precisely controlled by cell differentiation. Identifying new regulators and investigating their interactions provide insight into genetic networks defining pre-implantation development. We established a knockout mouse model of Dis3, an exosome associated ribonuclease. Homozygous Dis3 null embryos arrest at the morula stage of development. Using single-embryo RNA sequencing (RNA-seq), we observed persistence of Pou6f1 mRNA in homozygous null Dis3 embryos and that the cognate protein represses transcription of Nanog and Cdx2. The resultant defects in cell differentiation disrupt the morula-to-blastocyst transition and are embryonic lethal. Microinjection of Dis3 mRNA into zygotes rescues the phenotype. Point mutations of Dis3 ribonuclease in individual blastomeres prevents their incorporation into embryos. To overcome the paucity of embryos, we derived homozygous Dis3 null mouse embryonic stem cells to identify additional gene targets of POU6F1. Our findings delineate a regulatory pathway of DIS3-POU6F1 in pre-implantation mammalian embryogenesis.