The role of Fgf8 during cardiovascular development

描述（由申请人提供）：先天性心脏缺陷发生在近1%的人类活产。流出道畸形占这些畸形的近40%，如果不修复是致命的。心脏动脉极流出道和右心室的心肌来源于第二心野（SHF）内的前体群。我们发现成纤维细胞生长因子8 （Fgf8）在调节SHF行为和流出道心肌细胞身份的信号级联中起高作用。这些心肌细胞通常具有“非工作”特性，具有特殊的分泌、信号和细胞生物学功能，这些功能对流出道形态发生至关重要。在Fgf8条件小鼠突变体中，流出道心肌身份的许多方面都是“错误的”；在流出道重构过程中，突变心肌不执行下游内皮和神经嵴行为所需的分泌和信号功能。我们的数据支持最重要的假设，即外流道心肌前体正确分化和实现其独特身份需要SHF中的自分泌Fgf信号回路。本研究的目标是：确定Fgf8和Fgf受体消融后不同流出道（OFT）表型的基础；在SHF和咽内胚层中鉴定fgf8依赖性通路；确定Fgf8突变体OFT和右心室中shf来源的心肌细胞的身份；并发现Fgf8效应物在SHF中的直接转录靶点。公共卫生相关性：成纤维细胞生长因子8 （Fgf8）功能对胚胎心血管发育的重要性已得到证实，但这种信号蛋白调节心脏发育的分子和细胞机制尚不清楚。具体的研究目的是确定Fgf8信号传导到心脏前体如何控制其子代在心脏流出道中的身份。我们还试图确定Fgf8如何影响心肌细胞执行信号传导和分泌功能的能力，这些功能是流出道发育过程中邻近细胞类型行为所必需的。这项研究与人类出生缺陷和疾病高度相关，因为先天性心脏缺陷发生在近1%的人类活产婴儿中，而流出道畸形占近40%，如果不修复是致命的。

DESCRIPTION (provided by applicant): Congenital heart defects occur in nearly 1% of human live births. Outflow tract malformations comprise nearly 40% of these and are lethal if unrepaired. Myocardium at the arterial pole of the heart in the outflow tract and right ventricle derives from a precursor population within the second heart field (SHF). We have discovered that Fibroblast Growth Factor 8 (Fgf8) operates high in a signaling cascade that regulates SHF behavior and the identity of outflow tract myocardial cells. These myocardial cells normally have a "nonworking" identity with specialized secretory, signaling and cell biologic functions that are critical for outflow tract morphogenesis. In Fgf8 conditional mouse mutants, many aspects of outflow tract myocardial identity are "mistaken"; the mutant myocardium does not perform the secretory and signaling functions required for downstream endothelial and neural crest behaviors during outflow tract remodeling. Our data support the overriding hypothesis that an autocrine Fgf signaling loop in the SHF is required for outflow tract myocardial precursors to correctly differentiate and achieve their unique identity. The goals of this proposal are to: determine the bases for distinct outflow tract (OFT) phenotypes seen after Fgf8 and Fgf receptor ablation in different temporospatial domains; identify Fgf8-dependent pathways in the SHF and in pharyngeal endoderm; define the identity of SHF-derived myocardial cells in Fgf8 mutant OFT and right ventricle; and discover direct transcriptional targets of Fgf8 effectors in the SHF. PUBLIC HEALTH RELEVANCE: The importance of Fibroblast Growth Factor 8 (Fgf8) function for embryonic cardiovascular development is well established, but the molecular and cellular mechanisms whereby this signaling protein regulates development of the heart are still unknown. The specific research objective is to determine how Fgf8 signaling to heart precursors controls the identity of their progeny in the outflow tract of the heart. We also seek to determine how Fgf8 influences the ability of the myocardial cells to perform signaling and secretory functions that are required for behavior of adjacent cell types during outflow tract development. This research is highly relevant to human birth defects and disease because congenital heart defects occur in nearly 1% of human live births and malformations of the outflow tract comprise nearly 40% of these and are lethal if unrepaired.