Chibby, an antagonist of the Wnt/beta-catenin pathway, facilitates cardiomyocyte differentiation of murine embryonic stem cells.
BACKGROUND
Embryonic stem cell (ESC)-derived cardiomyocytes are anticipated to serve as a useful source for future cell-based cardiovascular disease therapies. Research emphasis is currently focused on determining methods to direct the differentiation of ESCs to a large population of cardiomyocytes with high purity. To this aim, understanding the molecular mechanisms that control ESC-to-cardiomyocyte differentiation should play a critical role in the development of this methodology. The Wnt/beta-catenin signaling pathway has been implicated in both embryonic cardiac development and in vitro ESC differentiation into cardiomyocytes. Chibby is a recently identified nuclear protein that directly binds to beta-catenin and antagonizes its transcriptional activity.


RESULTS
Chibby was ubiquitously expressed in early stages of ESC differentiation but upregulated during cardiomyocyte specification. Of interest, the Chibby gene promoter has multiple binding sites for the cardiac-specific homeodomain protein Nkx2.5, and its promoter activity was indeed positively regulated by Nkx2.5. Furthermore, overexpression of Chibby increased cardiac differentiation of ESCs, whereas loss of Chibby by RNAi impaired cardiomyocyte differentiation.


CONCLUSIONS
These data illustrate the regulation and function of Chibby in facilitating cardiomyocyte differentiation from ESCs. By revealing molecular mechanisms that control ESC-to-cardiomyocyte differentiation, this study will allow for the future development of technologies to improve cardiomyocyte differentiation from ESCs.
Singh
Amar M
AM
Department of Pathology, University of Florida College of Medicine, Box 100275, Gainesville, FL 32610, USA.
Li
Feng-Qian
FQ
Hamazaki
Takashi
T
Kasahara
Hideko
H
Takemaru
Ken-ichi
K
Terada
Naohiro
N
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
C473750:CBY1 protein, human; D002352:Carrier Proteins; C517894:Chibby protein, mouse; D009687:Nuclear Proteins; D051153:Wnt Proteins; D051176:beta Catenin