The role of FGF8 during cardiovascular development

描述（由申请人提供）：已创建FGF8缺陷小鼠，以评估该因子在咽部和心血管发育中的作用。95%的半胚突变小鼠存在大血管和流出道分离和排列缺陷；包括持续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嵴来源的间充质细胞，这些细胞分布于咽弓，并参与心脏流出道和大血管。我们假设Fgf8突变小鼠的心血管畸形是由咽弓外胚层和内胚层以及潜在的间质之间的Fgf8信号传导缺陷引起的。该项目的目的是确定FGF8参与心血管和咽部发育的分子和细胞途径。为了确定突变表型是否是由于弓上皮中FGF8的局部缺乏，我们的第一个目标是有条件地消融发育中的咽弓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在第四咽部弓血管发生中的作用。我们的第三个目标是通过表征FGF8亚型和条件突变体在咽神经嵴、中胚层和内胚层的基因表达、增殖和存活方面的改变，研究FGF8在咽和心血管发育过程中依赖于FGF8的分子和细胞途径。我们将鉴定FGF应答细胞的特定群体，并确定FGF8缺乏或缺乏如何影响它们的分化和行为。

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.