Canonical Wnt Pathway Controls mESC Self-Renewal Through Inhibition of Spontaneous Differentiation via β-Catenin/TCF/LEF Functions

Francesco Aulicino, Elisa Pedone, Francesco Sottile, Frederic Lluis, Lucia Marucci, Maria Pia Cosma*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

The Wnt/β-catenin signaling pathway is a key regulator of embryonic stem cell (ESC) self-renewal and differentiation. Constitutive activation of this pathway has been shown to increase mouse ESC (mESC) self-renewal and pluripotency gene expression. In this study, we generated a novel β-catenin knockout model in mESCs to delete putatively functional N-terminally truncated isoforms observed in previous knockout models. We showed that aberrant N-terminally truncated isoforms are not functional in mESCs. In the generated knockout line, we observed that canonical Wnt signaling is not active, as β-catenin ablation does not alter mESC transcriptional profile in serum/LIF culture conditions. In addition, we observed that Wnt signaling activation represses mESC spontaneous differentiation in a β-catenin-dependent manner. Finally, β-catenin (ΔC) isoforms can rescue β-catenin knockout self-renewal defects in mESCs cultured in serum-free medium and, albeit transcriptionally silent, cooperate with TCF1 and LEF1 to inhibit mESC spontaneous differentiation in a GSK3-dependent manner.
Original languageEnglish
Pages (from-to) 646-661
Number of pages16
JournalStem Cell Reports
Volume15
Issue number3
Early online date20 Aug 2020
DOIs
Publication statusPublished - 8 Sep 2020

Keywords

  • mESCs
  • Wnt
  • β-catenin
  • Ctnnb1
  • CRISPR
  • self-renewal
  • pluripotency
  • TCF
  • LEF
  • embryonic stem cells

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