Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling.
Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling.
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DOI：
10.1016/j.chembiol.2011.09.015
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发表时间：
2011-12-23
影响因子：
--
通讯作者：
Zhong TP
中科院分区：
文献类型：
--
作者：
Ni TT;Rellinger EJ;Mukherjee A;Xie S;Stephens L;Thorne CA;Kim K;Hu J;Lee E;Marnett L;Hatzopoulos AK;Zhong TP
我们已经开发了一种强大的体内小分子筛选，可以调节斑马鱼的心脏大小和心肌细胞的生成。从我们的筛选中发现的三种结构相关化合物（Cardionogen-1至-3）通过心肌增生扩大了正在发育的心脏的大小。心原处理的胚胎心肌细胞数量增加是由于心脏祖细胞的扩增。在斑马鱼胚胎和小鼠胚胎干（ES）细胞中，心原素治疗促进原肠胚形成期间和之后的心脏发生，而抑制原肠胚形成之前的心脏形成。可通过增加Wnt/β-catenin信号传导活性来拮抗心原诱导效应。我们证明了Cardionogen在小鼠胚胎干细胞和斑马鱼胚胎中抑制Wnt/β-catenin依赖性转录。Cardionogen可以在发育过程中挽救wnt8诱导的心肌细胞缺陷和心脏特异性表型。这些发现表明，针对心脏大小的体内小分子筛选可以发现具有心肌生成作用的化合物并确定潜在的靶标途径。
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 -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 inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/β-catenin signaling activity. We demonstrate that Cardionogen inhibits Wnt/β-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 targeted on heart size can discover compounds with cardiomyogenic effects and identify underlying target pathways.
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影响因子：
64.8
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0711507105
发表时间：
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影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
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作者：
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通讯作者：
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