Tissue-specific roles for Foxa2 during cardiac development and function

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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.