Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation
- INSERM, France
- CNRS, France
- Kumamoto University, Japan
- Institute for Molecular and Cellular Biology, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
Abstract
The establishment of separated pulmonary and systemic circulation in vertebrates, via the 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 an heart carrying the four congenital abnormalities defining the tetralogy of Fallot.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Daniel Sampaio Osorio
Funding
Agence Nationale de la Recherche (ANR-14-CE09-0006-04)
- Bruno Cadot
Ligue Contre le Cancer (PREAC2016.LCC)
- Vanessa Ribes
Agence Nationale de la Recherche (ANR-10-LABX-73)
- Mariana Valente
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments (APAFIS#4163-2016042809186990) were approved by the Animal Ethics Committee of Sorbonne University (Permit Number: A751320).
Reviewing Editor
- Richard P Harvey, Victor Chang Cardiac Research Institute, Australia
Version history
- Received: July 18, 2019
- Accepted: February 26, 2020
- Accepted Manuscript published: February 27, 2020 (version 1)
- Version of Record published: March 13, 2020 (version 2)
Copyright
© 2020, Darrigrand et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation
eLife 9:e50325.
https://doi.org/10.7554/eLife.50325
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