Abstract 789: Deficiency of Zic3 Affects Conduction System Development and Patterning
Introduction: Duplication or absence of parts of the specialized cardiac central conduction system is often identified in patients with heterotaxy syndrome. These abnormalities are thought to arise from disruption of the right/left axis patterning during fetal development. To investigate this hypothesis, we analyzed central conduction system development at multiple gestational ages in the Zic3 deficient murine heterotaxy model, with labeling of the conduction system provided by mating to the transgenic central conduction system (CCS)-LacZ marker mouse line.
Hypothesis: We hypothesize that deficiency of Zic3 will disrupt the developmental patterning of the central conduction system.
Methods and Results: A total of 114 CCS-LacZ/+ embryos were evaluated. Zic3 null; CCS-LacZ/+ mice were compared to Zic3 wild type; CCS-LacZ/+ embryos at E9.5 to E18.5. The anatomic position of the sinus node, AV node and the distal His-Purkinje system was evaluated.
Results: Direct comparison reveals disorganized and ambiguous arrangements throughout the CCS in Zic3 null mice, including the appearance of duplicated CCS structures. Furthermore, loss of Zic3 appears to affect CCS maturation, with retention of a more primitive conduction system pattern at late developmental stages. The severity and location of the CCS abnormalities coincided with the severity and location of associated structural heart disease.
Conclusion: CCS abnormalities in the Zic3 heterotaxy model are closely linked with associated abnormalities of cardiac structure and appear to be derived from right/left patterning abnormalities during fetal development. Potential mechanisms for this disruption include ambiguous patterning, duplication of tissue patterning and/or failure of progressive development with retention of earlier embryonic patterns. In conclusion, this mouse model provides a novel tool to dissect the mechanistic underpinnings of CCS development during right/left patterning.