Chen Hanying, Shi Shu, Acosta Lourdes, Li Weiming, Lu Jonathan, Bao Shideng, Chen Zhuang, Yang Zuocheng, Schneider Michael D, Chien Kenneth R, Conway Simon J, Yoder Mervin C, Haneline Laura S, Franco Diego, Shou Weinian
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Development. 2004 May;131(9):2219-31. doi: 10.1242/dev.01094. Epub 2004 Apr 8.
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 MEF2C) 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 BMP10, 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.
在心脏发生过程中，妊娠中期从心脏模式形成到心脏生长和腔室成熟这一关键转变受到干扰，常常会导致多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小梁增多。这种转变在小鼠胚胎中发生于胚胎第（E）9.0 - 9.5天，在人类胚胎中发生于E24 - 28天，对于发育中的心脏在应对不断增加的血流动力学负荷时维持正常的心脏生长和功能至关重要。虽然心室小梁形成和致密化是与这一转变相关的关键形态发生事件，但其分子和细胞机制目前尚不清楚。最初，心脏特异性细胞因子骨形态发生蛋白10（BMP10）被鉴定为在缺乏FK506结合蛋白12（FKBP12）的突变胚胎的肥厚小梁心脏中上调。为了确定BMP10在心脏发育过程中的生物学功能，我们构建了BMP10基因敲除小鼠。在此，我们描述了BMP10在调节心脏生长和腔室成熟中的重要作用。BMP10基因敲除小鼠在E9.0 - E9.5时表现出p57（kip2）的异位和上调表达以及心肌细胞增殖活性的显著降低。BMP10对于维持妊娠中期发育中心肌中几种关键心脏发生因子（如NKX2.5和MEF2C）的正常表达水平也是必需的。此外，BMP10条件培养基能够挽救培养中的BMP10基因敲除心脏。我们的数据表明了一条重要途径，该途径涉及BMP10、细胞周期调节蛋白和几种主要心脏转录因子之间的遗传相互作用，以协调妊娠中期心脏发生中的这一转变。这可能为理解结构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。
