β-Catenin Regulates Primitive Streak Induction through Collaborative Interactions with SMAD2/SMAD3 and OCT4 – University of Copenhagen

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28 April 2015

β-Catenin Regulates Primitive Streak Induction through Collaborative Interactions with SMAD2/SMAD3 and OCT4

Funa, Nina S.*, Karen A. Schachter*, Mads Lerdrup, Jenny Ekberg, Katja Hess, Nikolaj Dietrich, Christian Honoré, Klaus Hansen & Henrik Semb (2015). β-Catenin Regulates Primitive Streak Induction through Collaborative Interactions with SMAD2/SMAD3 and OCT4. Cell Stem Cell, doi:10.1016/j.stem.2015.03.008 (epub ahead of print on April 23, 2015). *authors contributed equally

Highlights

  • Wnt signaling induces primitive streak (PS) gene expression in hESCs
  • β-catenin binds upstream regulatory regions in most PS and neural crest genes
  • Direct interactions between β-catenin and SMAD2/SMAD3 mediate PS gene activation
  • OCT4 binds in proximity to β-catenin and SMAD2/SMAD3 sites to induce PS genes

Abstract

Canonical Wnt and Nodal signaling are both required for induction of the primitive streak (PS), which guides organization of the early embryo. The Wnt effector β-catenin is thought to function in these early lineage specification decisions via transcriptional activation of Nodal signaling. Here, we demonstrate a broader role for β-catenin in PS formation by analyzing its genome-wide binding in a human embryonic stem cell model of PS induction. β-catenin occupies regulatory regions in numerous PS and neural crest genes, and direct interactions between β-catenin and the Nodal effectors SMAD2/SMAD3 are required at these regions for PS gene activation. Furthermore, OCT4 binding in proximity to these sites is likewise required for PS induction, suggesting a collaborative interaction between β-catenin and OCT4. Induction of neural crest genes by β-catenin is repressed by SMAD2/SMAD3, ensuring proper lineage specification. This study provides mechanistic insight into how Wnt signaling controls early cell lineage decisions.