Bmp signaling is at the heart of vertebrate left-right asymmetry

Abstract

Bone morphogenetic protein (Bmp) signaling is vitally important in many aspects of cardiac development. These include cardiac induction and differentiation and establishing the L/R axis. In this thesis, we focus on the role of Bmp signaling in securing proper cardiac asymmetry, by (1) establishing correct L/R information that affects all organs, (2) directing asymmetric morphogenesis of the heart tube and (3) patterning the AVC myocardium to guarantee correct endocardial cushion formation. We demonstrated that Bmp signaling is required for determination of laterality by regulating asymmetric Nodal signaling (Spaw in the zebrafish). This left side-specific spaw expression is a fundamental feature of L/R asymmetry and we found that Bmp signaling controls Spaw in two ways. Perinodal Spaw signaling is required for spaw expression in the LPM and Bmp signaling limits spaw expression, restricted around the node, where it is within reach of the nodal flow. We also show that Bmp signaling secures spaw expression specifically on the left side of the LPM, by repressing spaw expression of the right side, most likely by the induction of Lefty1 in the embryonic midline. Furthermore, we appoint an additional role for Bmp signaling during later segmentation specifically in cardiac laterality, regulating cardiac jogging. We performed forward genetics screens to identify novel genes involved in the regulation of cardiac laterality specifically. Besides recovering known players in the TGF? superfamily, we have identified a potential new gene that will provide new evidence on the interpretation of L/R information at the level the heart specifically. Moreover, we provide evidence for a conserved mechanism in zebrafish in which Bmp signaling acts upstream of Tbx2b in maintaining and restricting the undifferentiated state within the AVC, crucial for correct valve formation. We also show that Wnt signaling acts upstream of Bmp signaling, leading to model of a linear pathway of Wnt-Bmp-Tbx2 in proper AVC differentiation. Altogether, governing correct Bmp signaling proves to be fundamental in constructing a functional heart.