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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717271.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Stepwise Clearance of Repressive Roadblocks Drives Cardiac Induction in Human ESCs
Authors:Rao, J.; Pfeiffer, M. J.; Frank, S.; Adachi, K.; Piccini, I.; Quaranta, R.; Arauzo-Bravo, M.; Schwarz, J.; Schade, D.; Leidel, S.; Scholer, H. R.; Seebohm, G.; Greber, B.
Date of Publication (YYYY-MM-DD):2015-12-29
Title of Journal:Cell Stem Cell
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Cardiac induction requires stepwise integration of BMP and WNT pathway activity. Human embryonic stem cells (hESCs) are developmentally and clinically relevant for studying the poorly understood molecular mechanisms downstream of these cascades. We show that BMP and WNT signaling drive cardiac specification by removing sequential roadblocks that otherwise redirect hESC differentiation toward competing fates, rather than activating a cardiac program per se. First, BMP and WNT signals pattern mesendoderm through cooperative repression of SOX2, a potent mesoderm antagonist. BMP signaling promotes miRNA-877 maturation to induce SOX2 mRNA degradation, while WNT-driven EOMES induction transcriptionally represses SOX2. Following mesoderm formation, cardiac differentiation requires inhibition of WNT activity. We found that WNT inhibition serves to restrict expression of anti-cardiac regulators MSX1 and CDX2/1. Conversely, their simultaneous disruption partially abrogates the requirement for WNT inactivation. These results suggest that human cardiac induction depends on multi-stage repression of alternate lineages, with implications for deriving expandable cardiac stem cells.
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany. Institute of Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Munster, 48149 Munster, Germany. Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain. Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany; Cells-in-Motion Cluster of Excellence, Faculty of Medicine, University of Munster, 48149 Munster, Germany. Technical University of Dortmund, 44227 Dortmund, Germany. Human Stem Cell Pluripotency Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany; Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany. Electronic address: boris.greber@mpi-muenster.mpg.de.
Identifiers:ISSN:1875-9777 (Electronic) %R 10.1016/j.stem.2015.11.0... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/26748419 [ID No:2]
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