Influence of BMP signaling on neural crest cells during heart outflow tract septation

The heart outflow tract (OFT) is originally a solitary tube, which is septated into the aortic and pulmonary artery (Pa) during embryonic development. This morphogenesis is regulated by the cardiac neural crest cells (cNCC), which colonize the OFT and condense towards the endocardium, triggering its rupture and the fromation of the two arteries. Investigations to identify the molecular cues controlling cNCC behaviour in the OFT mesenchyme have established the importance of the Bone Morphogenic Proteins (BMP). However, little is known on the molecular cascades triggered by BMP signaling responsible for the cNCC mediated OFT septation. To get insights into these molecular cascades, we decided to dissect the role of Dullard, a perinuclear phosphatase uncovered as a BMP intracellular signaling inhibitor, during OFT morphogenesis. Our results show that deletion of Dullard in the cNCC increases BMP intracellular signaling, leading to premature and asymmetric septation of the OFT, Pa obstruction and embryonic death. This BMP overactivation in the cNCC triggers the downregulation of mesenchymal markers and the upregulation of a cytokine called Sema3c, which in turn results in premature cNCC compaction at the endocardium. In addition, asymmetric differentiation of the distal subpulmonary myocardium contributes to asymmetrical rupture of the endocardium and Pa obstruction. Finally, our data converge to a model whereby graded BMP activity and Sema3c expression in the cNCC along the OFT axis set the tempo of OFT septation from its distal to its proximal regions. Hence, our findings reveal that fine tuning of BMP signaling levels in cNCC orchestrate OFT septation in time and space.