Expression of Foxm1 transcription factor in cardiomyocytes is required for myocardial development.
Expression of Foxm1 transcription factor in cardiomyocytes is required for myocardial development.
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DOI：
10.1371/journal.pone.0022217
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kalinichenko VV
中科院分区：
文献类型：
--
作者：
Bolte C;Zhang Y;Wang IC;Kalin TV;Molkentin JD;Kalinichenko VV
叉头盒M1 （Forkhead Box M1, Foxm1）是多种癌症器官形态发生和发展所必需的转录因子。尽管Foxm1 - / -小鼠中Foxm1的完全缺失由于多器官系统的严重异常而导致胚胎死亡，但心肌细胞对Foxm1的需求仍有待确定。本研究旨在阐明Foxm1信号在心脏发育中的心肌细胞自主作用。我们建立了一种新的小鼠模型，其中Foxm1从心肌细胞中被特异性删除（Nkx2.5-Cre/Foxm1fl/f小鼠）。在妊娠后期，心肌细胞中Foxm1的缺失足以破坏心脏形态发生并诱导胚胎死亡。Nkx2.5-Cre/Foxm1fl/fl心脏扩张，心室壁和室间隔变薄，心肌组织紊乱，最终导致心脏纤维化和毛细血管密度降低。在Nkx2.5-Cre/Foxm1fl/fl心脏中，由于Cdc25B、Cyclin B1、Plk-1、nMyc和p21cip1等多种细胞周期调控基因的表达改变，心肌细胞增殖减弱。此外，Foxm1缺陷心脏显示CaMKIIδ、Hey2和心肌素的表达降低，这是心脏功能和心肌生长的关键介质。我们的研究结果表明Foxm1在心肌细胞中的表达对于心脏正常发育至关重要，并且是心肌细胞增殖和心肌生长所必需的。
Forkhead Box M1 (Foxm1) is a transcription factor essential for organ morphogenesis and development of various cancers. Although complete deletion of Foxm1 in Foxm1−/− mice caused embryonic lethality due to severe abnormalities in multiple organ systems, requirements for Foxm1 in cardiomyocytes remain to be determined. This study was designed to elucidate the cardiomyocyte-autonomous role of Foxm1 signaling in heart development. We generated a new mouse model in which Foxm1 was specifically deleted from cardiomyocytes (Nkx2.5-Cre/Foxm1fl/f mice). Deletion of Foxm1 from cardiomyocytes was sufficient to disrupt heart morphogenesis and induce embryonic lethality in late gestation. Nkx2.5-Cre/Foxm1fl/fl hearts were dilated with thinning of the ventricular walls and interventricular septum, as well as disorganization of the myocardium which culminated in cardiac fibrosis and decreased capillary density. Cardiomyocyte proliferation was diminished in Nkx2.5-Cre/Foxm1fl/fl hearts owing to altered expression of multiple cell cycle regulatory genes, such as Cdc25B, Cyclin B1, Plk-1, nMyc and p21cip1. In addition, Foxm1 deficient hearts displayed reduced expression of CaMKIIδ, Hey2 and myocardin, which are critical mediators of cardiac function and myocardial growth. Our results indicate that Foxm1 expression in cardiomyocytes is critical for proper heart development and required for cardiomyocyte proliferation and myocardial growth.
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DOI：
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