The role of FGF8 during cardiovascular development

描述(由申请人提供)：FGF8缺陷小鼠已被创造出来，以评估该因子在咽部和心血管发育中的作用。我们在95%的低形态突变小鼠中发现了大血管和流出道的分隔和排列缺陷；这些缺陷包括永久性动脉干和主动脉弓中断。FGF8产生于中胚层周围的上皮细胞和神经脊来源的间充质细胞，这些细胞分布在咽弓，并对心脏流出道和大血管起作用。我们假设Fgf8突变小鼠的心血管畸形是由于咽弓外胚层和内胚层以及潜在间充质之间的FGF8信号缺陷所致。这个项目的目标是确定FGF8在心血管和咽部发育过程中参与的分子和细胞途径。为了确定突变表型是否是由于弓形上皮中FGF8的局部缺失，我们的第一个目标是有条件地去除发育中的咽弓的外胚层和内胚层中的FGF8。目的2研究FGF8基因突变体中主动脉弓动脉及其支持组织的形成和演化，明确FGF8在第四咽弓血管生成中的作用。我们的第三个目标是通过研究FGF8亚型突变体和条件性突变体中咽神经脊、中胚层和内胚层的基因表达、增殖和存活的变化，来研究在咽部和心血管发育过程中依赖于FGF8的分子和细胞途径。我们将确定特定的成纤维细胞生长因子反应细胞群，并确定它们的分化和行为如何因缺乏或缺乏FGF8而受到影响。 这些FGF8缺乏的动物所显示的表型阵列是非常完整的 与染色体22q11缺失相关的人类综合征的表型。描绘FGF8参与的通路不仅有助于我们确定这些通路如何引导咽结构、心脏流出道和大血管的正常发育，而且还将有助于我们深入了解这些发育程序的功能障碍如何导致由人类22G11区域基因缺失导致的常见和致命的出生缺陷。

DESCRIPTION (provided by applicant): FGF8 deficient mice have been created to evaluate the role of this factor in pharyngeal and cardiovascular development. Great vessel and outflow tract septation and alignment defects we re found in 95% of the hypomorphic mutant mice; these include persistent truncus arteriosus and interrupted aortic arch. FGF8 is produced in the epithelia surrounding the mesoderm and neural crest-derived mesenchymal cells that populate the pharyngeal arches, and contribute to the cardiac outflow tract and great vessels. We hypothesize that the cardiovascular malformations in Fgf8 mutant mice result from defective FGF8 signaling between the pharyngeal arch ectoderm and endoderm, and the underlying mesenchyme. The objective of this project is to define the molecular and cellular pathways in which FGF8 participates during cardiovascular and pharyngeal development. To determine if mutant phenotypes are due to local deficiency of FGF8 in the arch epithelia, our first aim is to conditionally ablate FGF8 in the ectoderm and endoderm of the developing pharyngeal arches. Aim 2 is to evaluate the formation and evolution of aortic arch arteries and supporting tissues in Fgf8 mutants and define the role of FGF8 during vasculogenesis in the fourth pharyngeal arch. Our third aim is to investigate the molecular and cellular pathways that are dependent on FGF8 during pharyngeal and cardiovascular development by characterizing the alterations in gene expression, proliferation, and survival of pharyngeal neural crest, mesoderm and endoderm in Fgf8 hypomorphic and conditional mutants. We will identify specific populations of FGF- responding cells and determine how their differentiation and behavior are affected by deficiency or absence of FGF8. The array of phenotypes displayed by these FGF8 deficient animals is a remarkably complete phenocopy of human syndromes associated with deletion of chromosome 22q11. Delineation of the pathways in which FGF8 is participates will not only help us to define how those pathways guide normal development of pharyngeal structures, the cardiac outflow tract and great vessels, but will also provide insight into how dysfunction of those developmental programs gives rise to the common and lethal array of birth defects that result from deletion of genes in the human 22g11 region.