Congenital Heart Disease (CHD), malformations of the heart present at birth, is the most common class of life-threatening birth defect (Hoffman (1995) [1], Gelb (2004) [2], Gelb (2014) [3]). A major research challenge is to elucidate the genetic determinants of CHD and mechanistically link CHD ontogeny to a molecular understanding of heart development. Although the embryonic origins of CHD are unclear in most cases, dysregulation of cardiovascular lineage specification, patterning, proliferation, migration or differentiation have been described (Olson (2004) [4], Olson (2006) [5], Srivastava (2006) [6], Dunwoodie (2007) [7], Bruneau (2008) [8]). Cardiac differentiation is the process whereby cells become progressively more dedicated in a trajectory through the cardiac lineage towards mature cardiomyocytes. Defects in cardiac differentiation have been linked to CHD, although how the complex control of cardiac differentiation prevents CHD is just beginning to be understood. The stages of cardiac differentiation are highly stereotyped and have been well-characterized (Kattman et al. (2011) [9], Wamstad et al. (2012) [10], Luna-Zurita et al. (2016) [11], Loh et al. (2016) [12], DeLaughter et al. (2016) [13]); however, the developmental and molecular mechanisms that promote or delay the transition of a cell through these stages have not been as deeply investigated. Tight temporal control of progenitor differentiation is critically important for normal organ size, spatial organization, and cellular physiology and homeostasis of all organ systems (Raff et al. (1985) [14], Amthor et al. (1998) [15], Kopan et al. (2014) [16]). This review will focus on the action of signaling pathways in the control of cardiomyocyte differentiation timing. Numerous signaling pathways, including the Wnt, Fibroblast Growth Factor, Hedgehog, Bone Morphogenetic Protein, Insulin-like Growth Factor, Thyroid Hormone and Hippo pathways, have all been implicated in promoting or inhibiting transitions along the cardiac differentiation trajectory. Gaining a deeper understanding of the mechanisms controlling cardiac differentiation timing promises to yield insights into the etiology of CHD and to inform approaches to restore function to damaged hearts.

先天性心脏病 (CHD) 是出生时出现的心脏畸形，是最常见的危及生命的出生缺陷类别（Hoffman (1995) [1]、Gelb (2004) [2]、Gelb (2014) [3] ). 一个主要的研究挑战是阐明 CHD 的遗传决定因素，并将 CHD 个体发育与心脏发育的分子理解联系起来。虽然在大多数情况下 CHD 的胚胎起源尚不清楚，但已经描述了心血管谱系规范、模式、增殖、迁移或分化的失调（Olson (2004) [4]、Olson (2006) [5]、Srivastava (2006) [ 6]、邓伍迪 (2007) [7]、布鲁诺 (2008) [8])。心脏分化是细胞在通过心脏谱系向成熟心肌细胞的轨迹中变得越来越专一的过程。心脏分化缺陷与冠心病有关，尽管心脏分化的复杂控制如何预防冠心病才刚刚开始被了解。心脏分化的阶段是高度刻板的，并且已经被很好地表征（Kattman 等人（2011）[9]，Wamstad 等人（2012）[10]，Luna-Zurita 等人（2016）[11]， Loh 等人 (2016) [12]、DeLaughter 等人 (2016) [13]）；然而，促进或延迟细胞通过这些阶段转变的发育和分子机制尚未得到深入研究。祖细胞分化的严格时间控制对于所有器官系统的正常器官大小、空间组织、细胞生理学和稳态至关重要（Raff 等人（1985）[14]，Amthor 等人（1998）[15]，Kopan等人（2014 年）[16]）。本综述将重点关注信号通路在控制心肌细胞分化时间方面的作用。许多信号通路，包括 Wnt、成纤维细胞生长因子、Hedgehog、骨形态发生蛋白、胰岛素样生长因子、甲状腺激素和 Hippo 通路，都与促进或抑制沿心脏分化轨迹的转变有关。更深入地了解控制心脏分化时间的机制有望深入了解先天性心脏病的病因，并为恢复受损心脏功能的方法提供信息。甲状腺激素和 Hippo 通路都与促进或抑制沿心脏分化轨迹的转变有关。更深入地了解控制心脏分化时间的机制有望深入了解先天性心脏病的病因，并为恢复受损心脏功能的方法提供信息。甲状腺激素和 Hippo 通路都与促进或抑制沿心脏分化轨迹的转变有关。更深入地了解控制心脏分化时间的机制有望深入了解先天性心脏病的病因，并为恢复受损心脏功能的方法提供信息。