Cirera-Salinas D Yu J Bodak M Ngondo RP Herbert KM Ciaudo C 2017 Mouse embryonic stem cells (mESCs) deficient for DGCR8, a key component of the microprocessor complex, present strong differentiation defects. However, the exact reasons impairing their commitment remain elusive. The analysis of newly generated mutant mESCs revealed that DGCR8 is essential for the exit from the pluripotency state. To dissociate canonical versus noncanonical functions of DGCR8, we complemented the mutant mESCs with a phosphomutant DGCR8, which restored microRNA levels but did not rescue the exit from pluripotency defect. Integration of omics data and RNA immunoprecipitation experiments established DGCR8 as a direct interactor of Tcf7l1 mRNA, a core component of the pluripotency network. Finally, we found that DGCR8 facilitated the splicing of Tcf7l1, an event necessary for the differentiation of mESCs. Our data reveal a new noncanonical function of DGCR8 in the modulation of the alternative splicing of Tcf7l1 mRNA in addition to its established function in microRNA biogenesis. https://sonar.ch/global/documents/27434 eng info:eu-repo/semantics/altIdentifier/doi/10.1083/jcb.201606073 info:eu-repo/semantics/altIdentifier/pmid/28100686 The Journal of cell biology. - 2017 Alternative Splicing Animals Cell Cycle Cell Differentiation Cell Line Cell Proliferation Embryonic Stem Cells Gene Knockdown Techniques Genotype Mice MicroRNAs Mutation Phenotype Phosphorylation Pluripotent Stem Cells Protein Binding RNA Interference RNA Precursors RNA, Messenger RNA-Binding Proteins Signal Transduction Time Factors Transcription Factor 7-Like 1 Protein Transfection Noncanonical function of DGCR8 controls mESC exit from pluripotency. http://purl.org/coar/resource_type/c_6501