title: A Regulatory Network Involving β-Catenin, e-Cadherin, PI3k/Akt, and Slug Balances Self-Renewal and Differentiation of Human Pluripotent Stem Cells In Response to Wnt Signaling.
abstract: The mechanisms underlying disparate roles of the canonical Wnt signaling pathway in maintaining self-renewal or inducing differentiation and lineage specification in embryonic stem cells (ESCs) are not clear. In this study, we provide the first demonstration that self-renewal versus differentiation of human ESCs (hESCs) in response to Wnt signaling is predominantly determined by a two-layer regulatory circuit involving β-catenin, E-cadherin, PI3K/Akt, and Slug in a time-dependent manner. Short-term upregulation of β-catenin does not lead to the activation of T-cell factor (TCF)-eGFP Wnt reporter in hESCs. Instead, it enhances E-cadherin expression on the cell membrane, thereby enhancing hESC self-renewal through E-cadherin-associated PI3K/Akt signaling. Conversely, long-term Wnt activation or loss of E-cadherin intracellular β-catenin binding domain induces TCF-eGFP activity and promotes hESC differentiation through β-catenin-induced upregulation of Slug. Enhanced expression of Slug leads to a further reduction of E-cadherin that serves as a β-catenin "sink" sequestering free cytoplasmic β-catenin. The formation of such a framework reinforces hESCs to switch from a state of temporal self-renewal associated with short-term Wnt/β-catenin activation to definitive differentiation. Stem Cells 2015;33:1419-1433.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Tyng-Shyan
authors.initials: TS
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Lilian
authors.initials: L
authors.lastname: Moalim-Nour
authors.forename: Deyong
authors.initials: D
authors.lastname: Jia
authors.forename: Jian
authors.initials: J
authors.lastname: Bai
authors.forename: Zemin
authors.initials: Z
authors.lastname: Yao
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D047428:Protein Kinase Inhibitors; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Differentiation; E-cadherin; Human embryonic stem cell; Self-renewal; Slug; Wnt; β-Catenin