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

eLife

Mariana Valente¹  Daniel S Osorio²  Jean-François Darrigrand³  Pauline Martinez³  Bruno Cadot³  Ryuichi Nishinakamura⁴  Glenda Comai⁵  Maxime Petit⁶  Vanessa Ribes⁷  Gilles Renault⁸  Carmen Marchiol⁸ 

[1] 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;Cytoskeletal Dynamics Lab, Institute for Molecular and Cellular Biology, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal;INSERM - Sorbonne Université UMR974 - Center for Research in Myology, Paris, France;Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan;Stem Cells and Development, Department of Developmental & Stem Cell Biology, CNRS UMR 3738, Institut Pasteur, Paris, France;Unité Lymphopoïèse – INSERM U1223, Institut Pasteur, Paris, France;Universite de Paris, Institut Jacques Monod, CNRS, Paris, France;Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France;

关键词: outflow tract;    neural crest cells;    Dullard;    BMP signaling;    mesenchymal-epithelial transition;   

DOI  :  10.7554/eLife.50325

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown