Vincentz Joshua W, Barnes Ralston M, Firulli Anthony B
Riley Heart Research Center, Wells Center for Pediatric Research, Division of Pediatric Cardiology, Department of Anatomy, Indiana Medical School, Indianapolis, IN 46202, USA.
Birth Defects Res A Clin Mol Teratol. 2011 Jun;91(6):485-94. doi: 10.1002/bdra.20796. Epub 2011 Apr 1.
Almost 15 years of careful study have established the related basic Helix-Loop-Helix (bHLH) transcription factors Hand1 and Hand2 as critical for heart development across evolution. Hand factors make broad contributions, revealed through animal models, to the development of multiple cellular lineages that ultimately contribute to the heart. They perform critical roles in ventricular cardiomyocyte growth, differentiation, morphogenesis, and conduction. They are also important for the proper development of the cardiac outflow tract, epicardium, and endocardium. Molecularly, they function both through DNA binding and through protein-protein interactions, which are regulated transcriptionally, posttranscriptionally by microRNAs, and posttranslationally through phosphoregulation. Although direct Hand factor transcriptional targets are progressively being identified, confirmed direct targets of Hand factor transcriptional activity in the heart are limited. Identification of these targets will be critical to model the mechanisms by which Hand factor bHLH interactions affect developmental pathways. Improved understanding of Hand factor-mediated transcriptional cascades will be necessary to determine how Hand factor dysregulation translates to human disease phenotypes. This review summarizes the insight that animal models have provided into the regulation and function of these factors during heart development, in addition to the recent findings that suggest roles for HAND1 and HAND2 in human congenital heart disease.
近15年的细致研究已证实，相关的碱性螺旋-环-螺旋（bHLH）转录因子Hand1和Hand2在整个进化过程中对心脏发育至关重要。通过动物模型发现，Hand因子对最终构成心脏的多种细胞谱系的发育有广泛贡献。它们在心室心肌细胞的生长、分化、形态发生和传导中发挥关键作用。它们对心脏流出道、心外膜和心内膜的正常发育也很重要。在分子层面，它们通过DNA结合以及蛋白质-蛋白质相互作用发挥功能，这些相互作用受到转录调控、微小RNA的转录后调控以及磷酸化的翻译后调控。尽管Hand因子的直接转录靶点正逐渐被确定，但在心脏中已确认的Hand因子转录活性的直接靶点却很有限。确定这些靶点对于构建Hand因子bHLH相互作用影响发育途径的机制模型至关重要。更好地理解Hand因子介导的转录级联反应对于确定Hand因子失调如何转化为人类疾病表型是必要的。本综述总结了动物模型在心脏发育过程中对这些因子的调控和功能所提供的见解，以及最近表明HAND1和HAND2在人类先天性心脏病中作用的研究发现。
