| Summary: | Malformations of the cardiovascular system are the most common type of birth defect in humans, affecting predominantly the formation of valves and septa. While many studies have addressed the role of specific genes during valve and septa formation, a global understanding is still largely incomplete. To address this deficit we have undertaken a genome-wide transcriptional profiling of the developing heart in the mouse. We generated and analyzed 19 Serial Analysis of Gene Expression (SAGE) libraries representing different regions of the mouse heart at multiple stages of embryonic development.
We speculated that genes important for heart valve development would be differentially expressed in the valve forming regions, and have dynamic temporal expression patterns. We used our dataset to identify a novel list of valve enriched genes. Using k-means cluster analysis we also uncovered 14 distinct temporal gene expression patterns in the developing valves. Unique temporal expression patterns were found to be enriched for specific signalling pathway members and functional categories such as signal transduction, transcription factor activity, proliferation and apoptosis.
The most highly expressed transcription factor within the developing valves was found to be Twist1. Analysis of gene expression changes in the Twist1 null developing valves revealed a novel phenotype consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. Our data suggests that TWIST1 directly activates valve specific and cell motility gene expression in the atrio-ventricular canal, while suppressing expression of valve maturation markers.
This work provides the first comprehensive temporal and spatial gene expression dataset for heart development during formation of the heart valves. It is a valuable resource for the elucidation of the molecular mechanisms underlying heart development.
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