Discovering Small Molecules that Promote Cardiomyocyte Generation by Modulating Wnt Signaling

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• 作者：Terri  ; T. Ni¹ ; ³ ; ⁷ ; Eric  ; J. Rellinger² ; ⁷ ; Amrita Mukherjee² ; ⁴ ; Shuying Xie¹ ; Lauren Stephens² ; Curtis  ; A. Thorne⁴ ; Kwangho Kim⁶ ; Jiangyong Hu² ; Ethan Lee⁴ ; Larry Marnett⁵ ; Antonis  ; K. Hatzopoulos² ; ⁴ ; Tao  ; P. Zhong¹ ; ² ; ⁴ ; ^{taozhong@fudan.edu.cn}
• 刊名：Chemistry & Biology
• 出版年：2011
• 出版时间：23 December 2011
• 年：2011
• 卷：18
• 期：12
• 页码：1658-1668
• 全文大小：1077 K

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ass=""h3"">Summary

We have developed a robust in?vivo small-molecule screen that modulates heart size and cardiomyocyte generation in zebrafish. Three structurally related compounds (Cardionogen-1 to Cardionogen-3) identified from our screen enlarge the size of the developing heart via myocardial hyperplasia. Increased cardiomyocyte number in Cardionogen-treated embryos is due to expansion of cardiac progenitor cells.?In zebrafish embryos and murine embryonic stem (ES) cells, Cardionogen treatment promotes cardiogenesis during and after gastrulation, whereas it inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/¦Â-catenin signaling activity. We?demonstrate that Cardionogen inhibits Wnt/¦Â-catenin-dependent transcription in murine ES cells and zebrafish embryos. Cardionogen can rescue Wnt8-induced cardiomyocyte deficiency and heart-specific phenotypes during development. These findings demonstrate that in?vivo small-molecule screens targeting heart size can reveal compounds with cardiomyogenic effects and identify underlying target pathways.