The molecular basis of cardiac differentiation control

先天性心脏病(CHD)是最常见的威胁生命的出生缺陷。 然而，数百个基因与CHD有关，这是异常的机制基础 导致冠心病的心脏形态发生在几乎所有病例中都是未知的。我们对刺猬的研究 在过去的十年中，信号与CHD在新的假说中达到顶峰，即 Hedgehog信号导致心脏祖细胞分化的常规控制失败 时间选择是导致冠心病的一个潜在原因。这项工作可能会突出分化的分子控制 计时是心脏发育的基石，分化计时缺陷是心脏发育的基础 冠心病病因学的候选机制。 这一建议是经过十年对潜在分子机制的研究形成的。 房室间隔缺损(AVSD)。房室间隔缺损是人类冠心病的一种严重形式，包括 5-10%的冠心病和更大比例的重大发病率和死亡率的病例1。我们 在此之前推动了对房室间隔理解的范式转变， 证明第二心区(SHF)需要纤毛刺猬(HH)信号 心脏祖细胞，而不是心脏本身，用于房室间隔。我们的实验室牵连到 纤毛、Hedgehog信号和心脏转录因子在房室间隔的SHF中的作用。在……里面 初步结果，我们最近的工作表明，HH信号控制着SHF前体 分化延迟和HH信号的去除导致了心脏的早熟分化。 在这项建议中，我们利用心脏分化控制的新范例来解决 心脏形态发生的遗传和分子机制。在具体目标1中，我们 直接询问心脏分化与心脏形态发生的关系 确定HH信号、心脏祖细胞分化控制和 心脏形态发生。在特定的目标2中，我们将研究叉头盒转录 因子基因Foxf1作为HH靶基因和SHF分化延迟的候选中介基因；以及 在具体目标3中，我们将确定SHF中发育谱系的多样性，其中 Lineages HH信号作为分化控制开关。如果成功，这些目标将 有助于从机制上理解AVSD并支持HH的新范式 差异化定时的信令控制。 好了！

Congenital Heart Disease (CHD) is the most common class of life-threatening birth defect. Whereas hundreds of genes have been implicated in CHD, the mechanistic basis of abnormal cardiac morphogenesis causing CHD is unknown in almost all cases. Our work on Hedgehog signaling and CHD over the last decade has culminated in the novel hypothesis that loss of Hedgehog signaling causes a failure of stereotypical control of cardiac progenitor differentiation timing as an underlying cause of CHD. This work may highlight molecular control of differentiation timing as a cornerstone of cardiac development with defects in differentiation timing as a candidate mechanism underlying CHD etiology. This proposal is formed from a decade of study of the molecular mechanisms underlying Atrioventricular septal defects (AVSDs). AVSDs are a serious form of CHD in humans, comprising 5-10% of all CHD and a greater proportion of cases with significant morbidity and mortality1. We have previously contributed to a paradigm shift in the understanding of AV septation, demonstrating that cilia-based Hedgehog (Hh) signaling is required in second heart field (SHF) cardiac progenitors, rather than in the heart itself, for AV septation. Our laboratory has implicated cilia, Hedgehog signaling, and cardiogenic transcription factors in the SHF for AV septation. In preliminary results, our recent work demonstrates that Hh signaling controls SHF progenitor differentiation delay and that removal of Hh signaling causes precocious cardiac differentiation. In this proposal we harness this novel paradigm for cardiac differentiation control to address the genetic and molecular mechanisms underlying cardiac morphogenesis. In Specific Aim 1, we directly interrogate the relationship between cardiac differentiation and cardiac morphogenesis to determine the relationship between Hh signaling, cardiac progenitor differentiation control, and cardiac morphogenesis. In Specific Aim 2, we will investigate the Forkhead box transcription factor gene Foxf1 as a Hh-target gene and candidate mediator of SHF differentiation delay; and in Specific Aim 3, we will identify the diversity of developmental lineages in the SHF and in which lineages Hh signaling acts as a differentiation control switch. If successful, these aims will contribute to a mechanistic understanding of AVSDs and support a novel paradigm for Hh signaling control of differentiation timing. !