Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation

• Main Authors: Jean-François Darrigrand, Mariana Valente, Glenda Comai, Pauline Martinez, Maxime Petit, Ryuichi Nishinakamura, Daniel S Osorio, Gilles Renault, Carmen Marchiol, Vanessa Ribes, Bruno Cadot
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-02-01
• Series: eLife
• Subjects: outflow tract; neural crest cells; Dullard; BMP signaling; mesenchymal-epithelial transition
• Online Access: https://elifesciences.org/articles/50325

The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac outflow tract (OFT) septation, is a sensitive developmental process accounting for 10% of all congenital anomalies. Neural Crest Cells (NCC) colonising the heart condensate along the primitive endocardial tube and force its scission into two tubes. Here, we show that NCC aggregation progressively decreases along the OFT distal-proximal axis following a BMP signalling gradient. Dullard, a nuclear phosphatase, tunes the BMP gradient amplitude and prevents NCC premature condensation. Dullard maintains transcriptional programs providing NCC with mesenchymal traits. It attenuates the expression of the aggregation factor Sema3c and conversely promotes that of the epithelial-mesenchymal transition driver Twist1. Altogether, Dullard-mediated fine-tuning of BMP signalling ensures the timed and progressive zipper-like closure of the OFT by the NCC and prevents the formation of a heart carrying the congenital abnormalities defining the tetralogy of Fallot.