Regionalized expression of Ankirin Repeat Domain 1 gene is essential to regulate multiple aspects of sinoatrial development and ventricular trabeculation

Cardiac Ankirin Repeat Protein (CARP), encoded by the Ankrd1 gene, is a multitasking mechanosensor protein involved in physiological and pathological remodeling of ventricular myocardium. A missense mutation (T116M-CARP), leading to increased stability and expression of the protein, has been identified in total abnormal pulmonary venous return (TAPVR) patients, thus suggesting a role of the gene in cardiac venous pole development . The goal of our study has been to assess the role of Ankrd1 in cardiac development. To this aim, we have re-investigated the expression profile of the gene in the developing mouse heart and we have generated two transgenic mouse lines overexpressing CARP or T116M-CARP, under the control of -MHC promoter. Our results show that Ankrd1 mRNA is highly regionalized in the early mouse heart, its expression being confided to domains delineating morphogenetic borders. Embryonic hearts overexpressing CARP wt or T116M presented a range of complex morphological defects, which included abnormal shape, size and positioning of the atria, interatrial septum, systemic and pulmonary veins, including TAPVR; additionally, cardiac chamber trabeculation was more extended. In conclusion, our results uncover for the first time a that CARP acts as a signaling molecule which defines the final shape, size and relative position of several cardiac components. Additionally, our data provide the missing developmental link between Ankrd1 and TAPVR occurrence in humans.