期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2012
卷号：109
期号：12
页码：4485-4490
DOI：10.1073/pnas.1118777109
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/{beta}-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/{beta}-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 {beta}-catenin signaling, which led us to postulate that Wnt/{beta}-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses {beta}-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates {beta}-catenin signaling in hESCs. Using a fluorescent reporter of {beta}-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 {beta}-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/{beta}-catenin signaling in the differentiation rather than self-renewal of hESCs.
