Tissue-specific roles for Foxa2 during cardiac development and function

描述(由申请人提供)：先天性心脏异常反映了最常见的出生缺陷形式，几乎存在于所有活产的1%。心脏传导系统的畸形通常会导致严重的疾病，可能会在没有任何预警的情况下危及生命，而涉及左右不对称建立缺陷的综合征通常表现为心脏结构异常，可能与成年后的生存不相容。转录因子Foxa2在影响心脏发育的内胚层和中胚层结构域中表达。通过将条件Foxa2缺失等位基因与组织特异性Cre表达系相结合获得的初步数据表明，Foxa2在心脏发生的多个不同方面发挥着关键作用，包括左-右模式、心脏传导和出生后心脏功能。具体目的1旨在探讨早期心脏发生过程中内胚层对Foxa2的需求。基因表达分析，包括原位杂交，将用于确定在该组织中介导Foxa2功能的下游靶点和分子途径。在特定目标2中，将描述中胚层特异性Foxa2突变体的出生后表型。这些研究将与表达分析相结合，旨在揭示心脏表型背后的分子缺陷，并确定Foxa2在这些途径中的作用。了解Foxa2调节心脏发育的途径将有助于深入了解涉及传导系统和左右不对称的人类心脏畸形的遗传病因。相关性：这项拟议的研究将使用突变小鼠来研究Foxa2基因是如何参与心脏的不对称发育的，该心脏具有独特的左右两方面的品质。我们还将研究Foxa2在特殊组织形成中的作用，这些组织传播和传导产生协调心跳的电脉冲。这些研究的结果将影响我们对出生缺陷的理解，在出生缺陷中，心脏形成异常或有不规则的心跳。

DESCRIPTION (provided by applicant): Congenital heart anomalies reflect the most common form of birth defect, present in almost 1 % of all live births. Malformations of the cardiac conduction system often lead to serious afflictions that can become life-threatening with little warning while syndromes involving defective establishment of left-right asymmetry are frequently manifest in abnormal cardiac structure and can be incompatible with survival into adulthood. The transcription factor Foxa2 is expressed in endodermal and mesodermal domains known to influence cardiac development. Preliminary data obtained by combining a conditional Foxa2 deletion allele with tissue-specific Cre-expressing lines suggest critical roles for Foxa2 in multiple distinct aspects of cardiogenesis, including left-right patterning, cardiac conduction, and postnatal heart function. Specific Aim 1 is designed to explore the requirement for Foxa2 in endoderm during early cardiogenesis. A gene expression analysis, including in situ hybridization, will be used to define the downstream targets and molecular pathways that mediate Foxa2 function in this tissue. In Specific Aim 2, the postnatal phenotype of mesodermal-specific Foxa2 mutants will be characterized. These studies will be coupled with an expression analysis designed to uncover the molecular defects that underlie the cardiac phenotype, and to define the role of Foxa2 in these pathways. Understanding the pathways within which Foxa2 regulates cardiac development will provide insight into the genetic etiology of human cardiac malformations involving the conduction system and left-right asymmetry. Relevance: The proposed study will use mutant mice to investigate how the Foxa2 gene is involved in the asymmetrical development of a heart with unique right and left-sided qualities. We will also examine the role of Foxa2 in the formation of specialized tissues that propagate and conduct the electrical impulses which generate a coordinated heart beat. The results of these studies will impact our understanding of birth defects in which the heart is formed abnormally or has an irregular beat.