| Life-threatening cardiac arrhythmias are responsible for a significant number of incidents of sudden cardiac death. A substantial part of these lethal arrhythmias is caused by developmental or acquired abnormalities associated with the cardiac conduction system and the nervous innervation of the heart. However, despite the severity of these disorders, little is known about the developmental and regulatory mechanisms underlying cardiac conduction system and innervation patterning. Recently, genome-wide micro-array analysis of the gene expression profiles of the cardiac conduction system and other myocardium revealed intriguing shared characteristics between conduction system and nervous system development. Among the highly enriched transcripts in the conduction system were Robo1, Robo2 and Slit2, which belong to the Robo-Slit signaling pathway. These genes have well established roles in nervous system development, but have not previously been identified in the cardiac conduction system. We hypothesize a role for these genes in the normal functional development of the cardiac conduction system itself, and in directing nervous innervation and angiogenesis specifically to the conduction system. To test this hypothesis, we will establish the function of Robo-Slit signaling in the cardiac conduction system and its innervation during development using multiple knock-out and over-expression analyses. |
