Foxp1 coordinates cardiomyocyte proliferation through both cell-autonomous and nonautonomous mechanisms
Foxp1 coordinates cardiomyocyte proliferation through both cell-autonomous and nonautonomous mechanisms
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DOI：
10.1101/gad.1929210
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发表时间：
2010-08-15
影响因子：
10.5
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
--
作者：
Zhang, Yuzhen;Li, Shanru;Morrisey, Edward E.
心肌细胞增殖在早期发育中是高的，并且随着妊娠而逐渐降低，导致损伤后成人心脏中缺乏强有力的心肌细胞增殖反应。关于细胞自主和非自主信号如何整合以调节发育过程中心肌细胞增殖的平衡，人们知之甚少。在这项研究中，我们表明，一个单一的转录因子，Foxp 1，可以控制心肌细胞增殖的平衡，在发展过程中，通过靶向不同的途径在内皮细胞和心肌。Foxp 1的内皮素缺失导致心脏中Fgf 3/Fgf 16/Fgf 17/Fgf 20表达降低，导致心肌细胞增殖减少。这种心肌增殖的丧失可以通过外源性Fgf 20来挽救，并且部分地通过Foxp 1对Sox 17的抑制来介导。相反，心肌特异性Foxp 1缺失导致心肌细胞增殖增加和分化降低，导致心肌质量增加和新生儿死亡。我们发现，Nkx2.5是Foxp 1抑制的直接靶点，并且在Foxp 1缺陷的心肌中Nkx2.5表达增加。此外，Nkx2.5的转基因过表达导致心肌细胞增殖增加和心室质量增加，类似于Foxp 1的心肌特异性损失。这些数据表明，Foxp 1通过Fgf配体和Nkx2.5表达的细胞系特异性调节来协调心肌细胞增殖和分化的平衡。
Cardiomyocyte proliferation is high in early development and decreases progressively with gestation, resulting in the lack of a robust cardiomyocyte proliferative response in the adult heart after injury. Little is understood about how both cell-autonomous and nonautonomous signals are integrated to regulate the balance of cardiomyocyte proliferation during development. In this study, we show that a single transcription factor, Foxp1, can control the balance of cardiomyocyte proliferation during development by targeting different pathways in the endocardium and myocardium. Endocardial loss of Foxp1 results in decreased Fgf3/Fgf16/Fgf17/Fgf20 expression in the heart, leading to reduced cardiomyocyte proliferation. This loss of myocardial proliferation can be rescued by exogenous Fgf20, and is mediated, in part, by Foxp1 repression of Sox17. In contrast, myocardial-specific loss of Foxp1 results in increased cardiomyocyte proliferation and decreased differentiation, leading to increased myocardial mass and neonatal demise. We show that Nkx2.5 is a direct target of Foxp1 repression, and Nkx2.5 expression is increased in Foxp1-deficient myocardium. Moreover, transgenic overexpression of Nkx2.5 leads to increased cardiomyocyte proliferation and increased ventricular mass, similar to the myocardial-specific loss of Foxp1. These data show that Foxp1 coordinates the balance of cardiomyocyte proliferation and differentiation through cell lineage-specific regulation of Fgf ligand and Nkx2.5 expression.