Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development
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AutorLandeira, David; Bagci, Hakan; Malinowski, Andrzej R.; Brown, Karen E.; Soza-Ried, Jorge; Feytout, Amelie; Webster, Zoe; Ndjetehe, Elodie; Cantone, Irene; Asenjo, Helena G.; Brockdorff, Neil; Carroll, Thomas; Merkenschlager, Matthias; Fisher, Amanda G.
Cell self-renewalEpiblast stem-cellsBeta-cateninGene expressionPolycom repressionPluripotency
Landeira, D.; et al. Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development. Cell Reports, 12(4): 573-586 (2015). [http://hdl.handle.net/10481/37290]
PatrocinadorThis study was supported by the Medical Research Council, the ERC (H.B. and J.S.-R.) (#294627), the HFSP (I.C.), and the Spanish Ministry of Economy and Competitiveness (D.L. and H.G.A.) (RYC-2012-10019; SAF2013-40891-R).
Jarid2 is part of the Polycomb Repressor complex 2 (PRC2) responsible for genome-wide H3K27me3 deposition. Unlike other PRC2-deficient embryonic stem cells (ESCs), however, Jarid2-deficient ESCs show a severe differentiation block, altered colony morphology, and distinctive patterns of deregulated gene expression. Here, we show that Jarid2−/− ESCs express constitutively high levels of Nanog but reduced PCP signaling components Wnt9a, Prickle1, and Fzd2 and lowered β-catenin activity. Depletion of Wnt9a/Prickle1/Fzd2 from wild-type ESCs or overexpression of Nanog largely phenocopies these cellular defects. Co-culture of Jarid2−/− with wild-type ESCs restores variable Nanog expression and β-catenin activity and can partially rescue the differentiation block of mutant cells. In addition, we show that ESCs lacking Jarid2 or Wnt9a/Prickle1/Fzd2 or overexpressing Nanog induce multiple ICM formation when injected into normal E3.5 blastocysts. These data describe a previously unrecognized role for Jarid2 in regulating a core pluripotency and Wnt/PCP signaling circuit that is important for ESC differentiation and for pre-implantation development.