The G protein-coupled receptor APJ/Aplnr has been widely reported to be involved in heart and vascular development and disease, but whether it contributes to organ left-right patterning is largely unknown. Here, we show that in zebrafish, coordinates organ LR patterning in an ligand-dependent manner using distinct mechanisms at different stages. During gastrulation and early somitogenesis, loss of function results in heart and liver LR asymmetry defects, accompanied by disturbed KV/cilia morphogenesis and disrupted left-sided expression in the LPM. In this process, only loss of function results in KV/cilia morphogenesis defect. In addition, only works as the early endogenous ligand to regulate KV morphogenesis, which then contributes to left-sided expression and subsequent organ LR patterning. The cascade regulates KV morphogenesis by enhancing the expression of , but not or , during KV development. At the late somite stage, both and contribute to the expression of in the trunk midline but do not regulate KV formation, and this role is possibly mediated by both endogenous ligands, and . In conclusion, our study is the first to identify a role for and their endogenous ligands in LR patterning, and it clarifies the distinct roles of and in orchestrating organ LR patterning.