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It is known that bone morphogenetic protein 4 (BMP‐4) has a diverse effect on ESCs. However, its precise mechanism in mouse ESCs is not fully understood. We evaluated the effect of BMP‐4 on ESC proliferation and its related signal cascades in this study. BMP‐4 significantly increased the level of [ 3 H]‐thymidine incorporation in time‐ (≥8 hours) and dose‐ (≥10 ng/ml) dependent manners. Additionally, BMP‐4 increased cyclin D1 and decreased p27 kip1  expression values in a time‐dependent manner. The increases in BMP‐4‐induced [ 3 H]‐thymidine incorporation and cyclin D1 expression were inhibited by the BMP‐4 receptor antagonist noggin. BMP‐4 increased Wnt1 expression. Wnt1 expression was attenuated by Smad4 small interfering RNA (siRNA), and BMP‐4‐induced cyclin D1 expression was inhibited by Smad4 and Wnt1 siRNAs. BMP‐4 also activated β‐catenin, which was blocked by Smad4 and Wnt1 siRNAs. In addition, BMP‐4 induced Akt phosphorylation. BMP‐4‐induced β‐catenin activation and cyclin D1 expression were attenuated by phosphatidyl inositol 3‐kinase (PI3K) siRNA and Akt inhibitor. Additionally, downregulation of Smad4, Wnt1, and PI3K expression by siRNA decreased the levels of pluripotency marker mRNAs of ESCs, including  Oct4 ,  Sox2 , and  FoxD3 . Our results suggested that BMP‐4‐induced [ 3 H]‐thymidine incorporation was significantly attenuated by Smad4, Wnt1, and PI3K knockdown. In conclusion, BMP‐4 contributed to the maintenance of cell proliferation and the pluripotent state by Smad, PI3K/Akt, and Wnt1/β‐catenin in mouse ESCs. STEM CELLS 2009;27:1858–1868

Smad, PI3K/Akt, and Wnt‐Dependent Signaling Pathways Are Involved in BMP‐4‐Induced ESC Self‐Renewal