miR-373 is regulated by TGFβ signaling and promotes mesendoderm differentiation in human Embryonic Stem Cells.
MicroRNAs (miRNAs) belonging to the evolutionary conserved miR-302 family play important functions in Embryonic Stem Cells (ESCs). The expression of some members, such as the human miR-302 and mouse miR-290 clusters, is regulated by ESC core transcription factors. However, whether miRNAs act downstream of signaling pathways involved in human ESC pluripotency remains unknown. The maintenance of pluripotency in hESCs is under the control of the TGFβ pathway. Here, we show that inhibition of the Activin/Nodal branch of this pathway affects the expression of a subset of miRNAs in hESCs. Among them, we found miR-373, a member of the miR-302 family. Proper levels of miR-373 are crucial for the maintenance of hESC pluripotency, since its overexpression leads to differentiation towards the mesendodermal lineage. Among miR-373 predicted targets, involved in TGFβ signaling, we validated the Nodal inhibitor Lefty. Our work suggests a crucial role for the interplay between miRNAs and signaling pathways in ESCs.
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA; Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome 00185, Italy.
Alessandro
A
Rosa
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
Marilena D
MD
Papaioannou
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
Joanna E
JE
Krzyspiak
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA. Electronic address: brvnlou@rockefeller.edu.
Ali H
AH
Brivanlou
D020413:3' Untranslated Regions; D002454:Cell Differentiation; D019070:Cell Lineage; D017077:Culture Media, Conditioned / Q000737:chemistry; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D055458:Left-Right Determination Factors / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D019076:Transgenes
D020413:3' Untranslated Regions; D017077:Culture Media, Conditioned; C526161:LEFTY1 protein, human; C411603:LEFTY2 protein, human; D055458:Left-Right Determination Factors; C532169:MIRN302A microRNA, human; C527114:MIRN373 microRNA, human; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1
Human Embryonic Stem Cells; Mesendoderm; TGFβ signaling; microRNAs