Akap12beta supports asymmetric heart development via modulating the Kupffer's vesicle formation in zebrafish

The vertebrate body plan is accomplished by left-right asymmetric organ development and the heart is a representative asymmetric internal organ which jogs to the left-side. Kupffer's vesicle (KV) is a spherical left-right organizer during zebrafish embryogenesis and is derived from a cluster of dorsal forerunner cells (DFCs). Cadherin1 is required for collective migration of a DFC cluster and failure of DFC collective migration by Cadherin1 decrement causes KV malformation which results in defective heart laterality. Recently, loss of function mutation of A-kinase anchoring protein 12 (AKAP12) is reported as a high-risk gene in congenital heart disease patients. In this study, we demonstrated the role of $akap12{\beta}$ in asymmetric heart development. The $akap12{\beta}$, one of the akap12 isoforms, was expressed in DFCs which give rise to KV and $akap12{\beta}$-deficient zebrafish embryos showed defective heart laterality due to the fragmentation of DFC clusters which resulted in KV malformation. DFC-specific loss of $akap12{\beta}$ also led to defective heart laterality as a consequence of the failure of collective migration by cadherin1 reduction. Exogenous $akap12{\beta}$ mRNA not only restored the defective heart laterality but also increased cadherin1 expression in $akap12{\beta}$ morphant zebrafish embryos. Taken together, these findings provide the first experimental evidence that $akap12{\beta}$ regulates heart laterality via cadherin1.