The role of FGF8 during cardiovascular development

描述（由申请人提供）：已经建立了FGF8缺陷小鼠以评价该因子在咽和心血管发育中的作用。大血管和流出道分隔和排列缺陷，我们发现在95%的亚形态突变小鼠，这些包括持续动脉干和中断的主动脉弓。FGF8产生于上皮细胞周围的中胚层和神经嵴来源的间充质细胞，填充咽弓，并有助于心脏流出道和大血管。我们推测，FGF8突变小鼠的心血管畸形是由于咽弓外胚层和内胚层之间的缺陷性FGF8信号传导，以及下面的间充质。本项目的目的是确定在心血管和咽部发育过程中FGF8参与的分子和细胞途径。为了确定突变表型是否是由于弓上皮中FGF8的局部缺乏，我们的第一个目的是有条件地消融发育中的咽弓的外胚层和内胚层中的FGF8。目的2是评估FGF8突变体主动脉弓动脉和支持组织的形成和演变，并确定FGF8在第四咽弓血管发生中的作用。我们的第三个目的是通过表征咽神经嵴的基因表达、增殖和存活的改变，中胚层和内胚层在Fgf8亚晶型和条件突变体中。我们将鉴定FGF反应细胞的特定群体，并确定它们的分化和行为如何受到FGF8缺乏或缺失的影响。 这些FGF8缺陷动物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。FGF8参与的途径的描述不仅有助于我们确定这些途径如何指导咽结构，心脏流出道和大血管的正常发育，而且还将提供对这些发育程序的功能障碍如何引起人类22g11区域基因缺失导致的常见和致命的出生缺陷的洞察。

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.