title: Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells.
abstract: Understanding pathways controlling cardiac development may offer insights that are useful for stem cell-based cardiac repair. Developmental studies indicate that the Wnt/beta-catenin pathway negatively regulates cardiac differentiation, whereas studies with pluripotent embryonal carcinoma cells suggest that this pathway promotes cardiogenesis. This apparent contradiction led us to hypothesize that Wnt/beta-catenin signaling acts biphasically, either promoting or inhibiting cardiogenesis depending on timing. We used inducible promoters to activate or repress Wnt/beta-catenin signaling in zebrafish embryos at different times of development. We found that Wnt/beta-catenin signaling before gastrulation promotes cardiac differentiation, whereas signaling during gastrulation inhibits heart formation. Early treatment of differentiating mouse embryonic stem (ES) cells with Wnt-3A stimulates mesoderm induction, activates a feedback loop that subsequently represses the Wnt pathway, and increases cardiac differentiation. Conversely, late activation of beta-catenin signaling reduces cardiac differentiation in ES cells. Finally, constitutive overexpression of the beta-catenin-independent ligand Wnt-11 increases cardiogenesis in differentiating mouse ES cells. Thus, Wnt/beta-catenin signaling promotes cardiac differentiation at early developmental stages and inhibits it later. Control of this pathway may promote derivation of cardiomyocytes for basic research and cell therapy applications.
authors.affiliation: Department of Pathology, Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ueno
authors.forename: Gilbert
authors.initials: G
authors.lastname: Weidinger
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Osugi
authors.forename: Aimee D
authors.initials: AD
authors.lastname: Kohn
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Golob
authors.forename: Lil
authors.initials: L
authors.lastname: Pabon
authors.forename: Hans
authors.initials: H
authors.lastname: Reinecke
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004627:Embryonic Induction / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005775:Gastrula / Q000196:embryology; D006321:Heart / Q000196:embryology*; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin