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

  1. Jean-François Darrigrand
  2. Mariana Valente
  3. Glenda Comai
  4. Pauline Martinez
  5. Maxime Petit
  6. Ryuichi Nishinakamura
  7. Daniel Sampaio Osorio
  8. Renault Gilles
  9. Carmen Marchiol
  10. Vanessa Ribes  Is a corresponding author
  11. Bruno Cadot  Is a corresponding author
  1. INSERM, France
  2. CNRS, France
  3. Kumamoto University, Japan
  4. 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

  1. Jean-François Darrigrand

    U974-Center for Research in Myology, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Mariana Valente

    U970 - Cellular, Molecular, and Physiological Mechanisms of Heart Failure, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Glenda Comai

    UMR 3738 - Department of Developmental & Stem Cell Biology, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3244-3378
  4. Pauline Martinez

    U974-Center for Research in Myology, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Maxime Petit

    U 1223 - Unité Lymphopoïèse, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8443-1531
  6. Ryuichi Nishinakamura

    Department of Kidney Development, Institute of Molecular Embryology & Genetics, Kumamoto University, Kumamoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Sampaio Osorio

    Cytoskeletal Dynamics Lab, Institute for Molecular and Cellular Biology, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4144-8189
  8. Renault Gilles

    Institut Cochin, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Carmen Marchiol

    Institut Cochin, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Vanessa Ribes

    UMR7592 - Institut Jacques Monod, CNRS, Paris, France
    For correspondence
    vanessa.ribes@ijm.fr
    Competing interests
    The authors declare that no competing interests exist.
  11. Bruno Cadot

    U974-Center for Research in Myology, INSERM, Paris, France
    For correspondence
    cadotbruno@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1888-3898

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.

Reviewing Editor

  1. Richard P Harvey, Victor Chang Cardiac Research Institute, Australia

Ethics

Animal experimentation: All animal experiments (APAFIS#4163-2016042809186990) were approved by the Animal Ethics Committee of Sorbonne University (Permit Number: A751320).

Version history

  1. Received: July 18, 2019
  2. Accepted: February 26, 2020
  3. Accepted Manuscript published: February 27, 2020 (version 1)
  4. 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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  1. Jean-François Darrigrand
  2. Mariana Valente
  3. Glenda Comai
  4. Pauline Martinez
  5. Maxime Petit
  6. Ryuichi Nishinakamura
  7. Daniel Sampaio Osorio
  8. Renault Gilles
  9. Carmen Marchiol
  10. Vanessa Ribes
  11. Bruno Cadot
(2020)
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

Share this article

https://doi.org/10.7554/eLife.50325

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