Wnt/β-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4

Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/β-caten...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-03, Vol.109 (12), p.4485-4490
Main Authors: Davidson, Kathryn C, Adams, Allison M, Goodson, Jamie M, McDonald, Circe E, Potter, Jennifer C, Berndt, Jason D, Biechele, Travis L, Taylor, Russell J, Moon, Randall T
Format: Article
Language:English
Subjects:
agonists
Animals
beta Catenin - metabolism
Biological Sciences
catenin
Cell Differentiation
Cell Lineage
Cell Proliferation
Coculture Techniques
Data processing
Differentiation
Embryo cells
embryonic stem cells
Embryonic Stem Cells - cytology
exposure pathways
Fluorescence
genes
Genes, Reporter
Humans
Mesoderm
Mice
Models, Biological
Oct-4 protein
Octamer Transcription Factor-3 - metabolism
Signal Transduction
Stem cells
Wnt protein
Wnt Proteins - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/β-catenin signaling is not active during hESC self-renewal. Inhibiting this pathway over multiple passages has no detrimental effect on hESC maintenance, whereas activating signaling results in loss of self-renewal and induction of mesoderm lineage genes. Following exposure to pathway agonists, hESCs exhibit a delay in activation of β-catenin signaling, which led us to postulate that Wnt/β-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses β-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates β-catenin signaling in hESCs. Using a fluorescent reporter of β-catenin signaling in live hESCs, we observe that the reporter is activated in a very heterogeneous manner in response to stimulation with Wnt ligand. Sorting cells on the basis of their fluorescence reveals that hESCs with elevated β-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/β-catenin signaling in the differentiation rather than self-renewal of hESCs.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1118777109