Establishing cardiac left‐right asymmetry

The developing heart undergoes left‐right (LR) asymmetric movements that are critical for establishing normal cardiac form and function. In several vertebrates, a group of motile cilia, referred to as ‘LR cilia,’ create an asymmetric fluid flow necessary for establishing molecular signals that instruct asymmetric heart morphogenesis. However, how LR cilia generate asymmetric signals and how these signals are translated into anatomical asymmetries remain poorly understood. We are using zebrafish to characterize mechanisms involved in cardiac LR development. Taking a reverse genetic approach, we have identified multiple roles for Rho GTPase signaling. Rho GTPases, which signal through effector proteins, regulate actomyosin cytoskeletal dynamics to control cell behavior. Interfering with Rho pathway components using dominant negative proteins or antisense morpholinos disrupted formation of LR cilia and altered the cellular architecture of the LR ciliated epithelium, located in an organ called Kupffer's vesicle. Live imaging of embryos expressing GFP in Kupffer's vesicle revealed Rho signaling controls cell morphologies that mediate Kupffer's vesicle development. In addition, it appears Rho signaling plays an independent role in the heart during asymmetric morphogenesis. These results implicate cytoskeletal dynamics in several steps of cardiac LR development.