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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.

Original publication

DOI

10.1016/j.celrep.2015.06.060

Type

Journal article

Journal

Cell Rep

Publication Date

28/07/2015

Volume

12

Pages

573 - 586

Keywords

Adaptor Proteins, Signal Transducing, Animals, Blastocyst, Cell Differentiation, Cells, Cultured, Embryonic Stem Cells, Frizzled Receptors, Gene Expression Regulation, Developmental, Homeodomain Proteins, LIM Domain Proteins, Mice, Nanog Homeobox Protein, Polycomb Repressive Complex 2, Wnt Proteins, Wnt Signaling Pathway, beta Catenin