Biphasic role for Wnt/beta-catenin signaling in cardiac specification in zebrafish and embryonic stem cells.
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.
Ueno
Shuichi
S
Department of Pathology, Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA.
Weidinger
Gilbert
G
Osugi
Tomoaki
T
Kohn
Aimee D
AD
Golob
Jonathan L
JL
Pabon
Lil
L
Reinecke
Hans
H
Moon
Randall T
RT
Murry
Charles E
CE
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*
C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin