INSERM - Sorbonne Université UMR974 - Center for Research in Myology, Paris, France.
Cellular, Molecular, and Physiological Mechanisms of Heart Failure team, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737, Paris, France.
Elife. 2020 Feb 27;9:e50325. doi: 10.7554/eLife.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 and conversely promotes that of the epithelial-mesenchymal transition driver . 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.
脊椎动物通过心流出道（OFT）分隔建立肺循环和体循环的分离是一个敏感的发育过程，占所有先天性异常的 10%。神经嵴细胞（NCC）沿着原始心内膜管殖民心脏冷凝物，并迫使它分裂成两个管。在这里，我们表明，NCC 聚集沿着 OFT 远-近端轴逐渐减少，遵循 BMP 信号梯度。Dullard，一种核磷酸酶，调整 BMP 梯度幅度并防止 NCC 过早凝聚。Dullard 维持转录程序，为 NCC 提供间充质特征。它减弱了聚集因子的表达，相反促进了上皮-间充质转化驱动因子的表达。总之，Dullard 介导的 BMP 信号精细调节确保了 NCC 的 OFT 以拉链状的方式定时和渐进地关闭，并防止了携带定义法洛四联症的先天性异常的心脏的形成。
