Transcriptional Profiling of Early Cardiac Development
Masino, Amanda M.
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Cardiogenesis is an intricate process that spans nearly the entire developmental history of the mammal. A thorough comprehension of the molecular interactions that direct cardiac development will improve our ability to understand and treat cardiovascular diseases. The earliest stages of heart development are of particular interest because it is during these stages that patterning of cardiac structure appears critical. Traditionally, studies of these early developmental processes have been conducted on chicken, fish, or frog embryos due to ease of manipulation. More recently, however, the wide availability of tools designed to manipulate and isolate cell populations in the murine embryo, together with the advent of technologies for studying gene expression at the transcriptome level, have allowed for detailed study of these events in mammalian systems. I applied transgenic labeling and flow cytometry to isolate cardiac cell populations from early mouse embryos. Transcriptome analysis of these cell populations allowed me to characterize unique gene expression patterns and identify novel genetic pathways relevant to cardiac development. I undertook three interrelated studies. First, I completed a survey of the transcriptome of the developing heart at the cardiac crescent, linear heart tube, and looped heart tube stages to describe molecular signatures in the developing heart. I defined gene expression patterns unique to the cardiac crescent and looped heart, and identified novel markers of the developing heart. The second study focused on defining the transcriptional network of a key cardiac regulator, Nkx2.5. I identified transcripts misexpressed during the early development of Nkx2.5 null embryos, including the Nkx2.5 transcriptional targets ETSrelated transcription factor 71 and vascular cell adhesion molecule. Lastly, I characterized Nkx2.5-dependent left-right patterning in the cardiac crescent that revealed early specification of chamber myocardial lineages. In conclusion, these studies have elucidated the molecular profile of the developing heart and provided novel insights into the earliest stages of cardiac development.