β-Catenin Regulates Primitive Streak Induction through Collaborative Interactions with SMAD2/SMAD3 and OCT4.
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.
The Danish Stem Cell Centre (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark; Lund Stem Cell Center, Faculty of Medicine, Lund University, 22100 Lund, Sweden.
Nina S
NS
Funa
The Danish Stem Cell Centre (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark.
Karen A
KA
Schachter
Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen Biocenter, 2200 Copenhagen N, Denmark.
Mads
M
Lerdrup
Lund Stem Cell Center, Faculty of Medicine, Lund University, 22100 Lund, Sweden.
Jenny
J
Ekberg
The Danish Stem Cell Centre (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark; Lund Stem Cell Center, Faculty of Medicine, Lund University, 22100 Lund, Sweden.
Katja
K
Hess
Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen Biocenter, 2200 Copenhagen N, Denmark.
Nikolaj
N
Dietrich
Department of Stem Cell Biology, Novo Nordisk A/S, 2760 Maaloev, Denmark.
Christian
C
Honoré
Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, Copenhagen Biocenter, 2200 Copenhagen N, Denmark.
Klaus
K
Hansen
The Danish Stem Cell Centre (DanStem), University of Copenhagen, 2200 Copenhagen N, Denmark; Lund Stem Cell Center, Faculty of Medicine, Lund University, 22100 Lund, Sweden. Electronic address: semb@sund.ku.dk.
Henrik
H
Semb
D001483:Base Sequence; D002460:Cell Line; D019070:Cell Lineage; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009432:Neural Crest / Q000166:cytology; D055457:Nodal Protein / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D054240:Primitive Streak / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
D055457:Nodal Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051176:beta Catenin