BMP10 is essential for maintaining cardiac growth during murine cardiogenesis
BMP10 is essential for maintaining cardiac growth during murine cardiogenesis
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DOI：
10.1242/dev.01094
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发表时间：
2004-05-01
期刊：
影响因子：
4.6
通讯作者：
Shou, WN
中科院分区：
文献类型：
--
作者：
Chen, HY;Shi, S;Shou, WN
在心脏发生过程中，孕中期从心脏形态到心脏生长和心腔成熟的关键转变的扰动往往会导致各种类型的先天性心脏病，如室间隔缺损(VSD)、心肌致密化不全和心室过度小梁形成。这种转变发生在小鼠胚胎的9.0-9.5天和人类胚胎的E24-28天，对发育中的心脏维持正常的心脏生长和功能是至关重要的，以响应不断增加的血流动力学负荷。虽然，脑室小梁和致密化是与这一转变相关的关键的形态发生事件，但其分子和细胞机制目前尚不清楚。最初，心脏限制性细胞因子骨形态发生蛋白10(BMP10)被证实在FK506结合蛋白12(FKBP12)缺陷的突变胚胎的超小梁心脏中上调。为了确定BMP10在心脏发育过程中的生物学功能，我们产生了BMP10缺陷小鼠。在这里，我们描述了BMP10在调节心脏生长和心腔成熟中的重要作用。BMP10基因缺失的小鼠在E9.0-E9.5表现出p57(Kip2)的异位表达和升高，心肌细胞的增殖活性显著降低。在妊娠中期，BMP10也是维持几个关键的致心因子(如NKX2.5和NIEF2C)在发育中的心肌中正常表达所必需的。此外，BMP10条件培养液能够挽救培养中BMP10缺陷的心脏。我们的数据表明，在妊娠中期，BNIP10、细胞周期调节蛋白和几个主要的心脏转录因子之间的遗传相互作用是协调心脏发生的这一转变的重要途径。这可能为了解结构性和功能性先天性心脏缺陷的发病机制提供一个潜在的机制。
During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition, which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57(kip2) and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and NIEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BNIP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.