Transcriptional control of cardiac neural crest cells condensation and outflow tract septation by the Smad1/5/8 inhibitor Dullard

Summary The establishment of separated pulmonary and systemic circulations in vertebrates, via the cardiac outflow tract (OFT) septation, stands as a sensitive developmental process accounting for 10% of all congenital anomalies. It relies on the Neural Crest Cells (NCC) colonization of the heart, whose condensation along the endocardial wall forces its scission into two tubes. Here, we show that NCC aggregation starts more pronounced at distal OFT areas than at proximal sites. This spatial organisation correlates with a decreasing distal-proximal gradient of BMP signalling. Dullard, a nuclear phosphatase, sets the BMP gradient amplitude and prevents NCC premature condensation. Dullard is required for maintaining transcriptional programmes providing NCC with mesenchymal traits. It attenuates the adhesive cue Sema3c levels and conversely promotes the epithelial-mesenchymal transition driver Twist1 expression. Altogether, Dullard mediated fine-tuning of BMP signalling ensures the timed and progressive condensation of NCC and rules a zipper-like closure of the OFT.