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.