Cardiac conduction system (CCS) abnormalities are an important clinical problem in the United States, with sick sinus syndrome alone accounting for more than 60% of the 170,000 pacemakers implanted each year. Although implantation of Electronic pacemaker is an effective palliative procedure, finding a cure to these diseases is imperative. Understanding the physiological pacemaker, the sinoatrial node, is a fundamental first step to finding an effective cure.
While the molecular identity of the sinoatrial node, its subdivisions and other components of the cardiac conduction system have been relatively well established, the mechanisms behind the origin and development of the sinoatrial node, the leading pacemaker, are yet unknown.
The studies in this dissertation characterize the four CCS marker mice based on the molecular signature of the SAN, to elucidate their utility in the understanding of the SAN developmental process. We have demonstrated that the marker mice used in the study of the cardiac conduction system, robustly mark the atrioventricular conduction system, but fail to mark the adult sinoatrial node. This reduces the utility of these mice in the study of the sinoatrial node while reaffirming their effectiveness in the study of the AVCS.
Cardiac connexin Cx45 has a CCS specific expression and hence understanding its regulatory network is of interest to this body of work. In order to identify this network, studies were done to define the proximal promoter of Cx45 and the regulation of Cx45 expression by Tbx3 was undertaken. We found that Cx45 was post-transcriptionally regulated and the isoform containing exon1a was most predominant in the sinoatrial node. Reduction in Tbx3 also resulted in a decrease in Cx45 expression. Two transcription factors, Shox2 and Tbx3 deletion mice have been shown to be important in the development of the sinus venosus and SAN. We investigated the effects on the embryonic sinoatrial node due to targeted deletion of Shox2 gene. We found that Shox2 is important in the inhibition of Nkx2.5 expression in the sinus venosus. If Nkx2.5, one of the primary genes involved in the specification of the working myocardium, is mis-expressed in the sinus venosus will cause the atrialization of the sinoatrial node. Atrialized sinoatrial node is dysfunctional and will progressively fail to pace leading to intrauterine death. Increasing the understanding of the sinoatrial node development will provide insights to developing a viable biological pacemaker.