Transcriptional regulation of cardiac morphogenesis

摘要 先天性心脏病(CHD)是最常见的出生缺陷。在各种CHD中，单心室 由心室形态发生改变引起的表型临床预后最差。CHDS那个 存在心室形态发生缺陷，导致充氧和去氧血液混合 通过室间隔缺陷(VSD)和/或收缩功能受损，这两者都限制了活力。 目前，对该病的分子机制和细胞病因学了解甚少。 多种形式的室性心脏病。 Hand1在发育中的左心室(LV)心肌和心肌袖套(MC)中表达 胚胎期(E)E8.5~E13.5。基因打靶模型证实Hand1是 左心室发育正常。我们证明，心肌细胞缺失Hand1会导致存活的小鼠出现 CHDS影响左心室形态。最近，在被诊断为HAND1突变的患者中被发现 患有先天性心脏病。这些HAND1基因突变表现为蛋白质内的移码或无义突变 编码域，并被报道为本质上是体细胞的，因为HAND1的种系突变被假设为 胚胎致死。与所有基因一样，Hand1通过位于 在保守的非编码序列(CNS)中，Hand1转录的5‘和3’都存在 开始站点。中枢神经系统基因突变通过心脏缺陷影响Hand1功能的观点 转录调控元件是一个在很大程度上未被探索的假说，它可能提供一种机制 人类先天性心脏病中的遗传性心脏功能丧失。 相关性 导致脑室表型的CHDS的临床结果最差。因此，了解了 导致CHDS导致心室形态发生改变的病因和分子机制 每年使数以千计的儿科患者受益的潜力。Hand1在心肌细胞中起关键作用 构建模式并深入了解这种未被研究的发育的细胞和分子机制 这一过程将对发展冠心病患者的非手术治疗有很大的好处。

ABSTRACT Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of ventricular CHDs. Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC) between embryonic day (E) E8.5 and E13.5. Gene targeting models establish that Hand1 is required for normal LV development. We show that cardiomyocyte deletion of Hand1 results in surviving mice that present with CHDs effecting LV morphology. Recently, HAND1 mutations have been identified in patients diagnosed with CHDs. These HAND1 gene mutations manifest as frameshift or nonsense mutations within the protein coding domains and are reported to be somatic in nature, as germline mutations in HAND1 are assumed to be embryonic lethal. Like all genes, Hand1 is transcriptionally regulated through cis-element enhancers located within Conserved Non-coding Sequences (CNS) that are present both 5' and 3' to the Hand1 transcriptional start site. The notion that CNS gene mutations affecting the function of Hand1 through defects in cardiac transcriptional regulatory elements is a largely unexplored hypothesis that could provide a mechanism for heritable Hand1 cardiac loss-of-function in human CHDs. RELEVANCE CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular morphogenesis has the potential to benefit thousands of pediatric patients annually. Hand1 plays a key role in cardiomyocyte patterning and gaining insight into the cellular and molecular mechanism of this understudied developmental process will have a great benefit to developing non-surgical treatments for CHD patients.