1. Developmental Biology
Download icon

Hox-dependent coordination of mouse cardiac progenitor cell patterning and differentiation

  1. Sonia Stefanovic
  2. Brigitte Laforest
  3. Jean-Pierre Desvignes
  4. Fabienne Lescroart
  5. Laurent Argiro
  6. Corinne Maurel-Zaffran
  7. David Salgado
  8. Elise Plaindoux
  9. Christopher De Bono
  10. Kristijan Pazur
  11. Magali Théveniau-Ruissy
  12. Christophe Béroud
  13. Michel Puceat
  14. Anthony Gavalas
  15. Robert G Kelly
  16. Stephane Zaffran  Is a corresponding author
  1. Aix Marseille University, France
  2. University of Chicago, United States
  3. Aix-Marseille Université, France
  4. CNRS-AMU, France
  5. Technische Universität Dresden, Germany
Research Article
  • Cited 10
  • Views 1,587
  • Annotations
Cite this article as: eLife 2020;9:e55124 doi: 10.7554/eLife.55124

Abstract

Perturbation of addition of second heart field (SHF) cardiac progenitor cells to the poles of the heart tube results in congenital heart defects (CHD). The transcriptional programs and upstream regulatory events operating in different subpopulations of the SHF remain unclear. Here, we profile the transcriptome and chromatin accessibility of anterior and posterior SHF sub-populations at genome-wide levels and demonstrate that Hoxb1 negatively regulates differentiation in the posterior SHF. Spatial mis-expression of Hoxb1 in the anterior SHF results in hypoplastic right ventricle. Activation of Hoxb1 in embryonic stem cells arrests cardiac differentiation, whereas Hoxb1-deficient mouse embryos display premature cardiac differentiation. Moreover, ectopic differentiation in the posterior SHF of embryos lacking both Hoxb1 and its paralog Hoxa1 results in atrioventricular septal defects. Our results show that Hoxb1 plays a key role in patterning cardiac progenitor cells that contribute to both cardiac poles and provide new insights into the pathogenesis of CHD.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2 and 3.

Article and author information

Author details

  1. Sonia Stefanovic

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  2. Brigitte Laforest

    Department of Pediatrics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6919-8922

  3. Jean-Pierre Desvignes

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  4. Fabienne Lescroart

    INSERM, MMG, U1251, Aix-Marseille Université, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4942-7921

  5. Laurent Argiro

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  6. Corinne Maurel-Zaffran

    IBDM, CNRS-AMU, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  7. David Salgado

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  8. Elise Plaindoux

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  9. Christopher De Bono

    IBDM, CNRS UMR7288, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  10. Kristijan Pazur

    Paul Langerhans Institute Dresden of Helmholtz Centre Munich, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.

  11. Magali Théveniau-Ruissy

    INSERM U1251 Marseille Medical Genetics, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7346-7096

  12. Christophe Béroud

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  13. Michel Puceat

    INSERM U1251 Marseille Medical Genetics, Aix Marseille University, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9055-7563

  14. Anthony Gavalas

    Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.

  15. Robert G Kelly

    CNRS UMR 7288, Aix-Marseille Université, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.

  16. Stephane Zaffran

    INSERM, MMG, U1251, Aix Marseille University, Marseille, France
    For correspondence
    stephane.zaffran@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0811-418X

Funding

Agence Nationale de la Recherche (ANR-13-BSV2-0003)

  • Michel Puceat
  • Robert G Kelly
  • Stephane Zaffran

Agence Nationale de la Recherche (ANR-18-CE13-0011)

  • Robert G Kelly
  • Stephane Zaffran

Fondation Lefoulon Delalande

  • Sonia Stefanovic
  • Fabienne Lescroart

Association Française contre les Myopathies (MNH-Decrypt)

  • Stephane Zaffran

Fondation pour la Recherche Médicale

  • Brigitte Laforest

Fondation pour la Recherche Médicale (DEQ20150331717)

  • Robert G Kelly

European Commission (H2020-MSCA-IF-2014)

  • Sonia Stefanovic

Fondation Leducq (Research Equipment and Technological Platform Awards)

  • Michel Puceat
  • Robert G Kelly
  • Stephane Zaffran

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal procedures were carried out under protocols approved by a national appointed ethical committee for animal experimentation (Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche; Authorization N{degree sign}32-08102012).

Reviewing Editor

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

Publication history

  1. Received: January 13, 2020
  2. Accepted: August 16, 2020
  3. Accepted Manuscript published: August 17, 2020 (version 1)
  4. Version of Record published: September 1, 2020 (version 2)

Copyright

© 2020, Stefanovic 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.

Metrics

  • 1,587
    Page views
  • 216
    Downloads
  • 10
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Developmental Biology
    2. Evolutionary Biology

    Single cell RNA sequencing of the Strongylocentrotus purpuratus larva reveals the blueprint of major cell types and nervous system of a non-chordate deuterostome

    Periklis Paganos et al.
    Research Article

    Identifying the molecular fingerprint of organismal cell types is key for understanding their function and evolution. Here, we use single cell RNA sequencing (scRNA-seq) to survey the cell types of the sea urchin early pluteus larva, representing an important developmental transition from non-feeding to feeding larva. We identify 21 distinct cell clusters, representing cells of the digestive, skeletal, immune, and nervous systems. Further subclustering of these reveal a highly detailed portrait of cell diversity across the larva, including the identification of neuronal cell types. We then validate important gene regulatory networks driving sea urchin development and reveal new domains of activity within the larval body. Focusing on neurons that co-express Pdx-1 and Brn1/2/4, we identify an unprecedented number of genes shared by this population of neurons in sea urchin and vertebrate endocrine pancreatic cells. Using differential expression results from Pdx-1 knockdown experiments, we show that Pdx1 is necessary for the acquisition of the neuronal identity of these cells. We hypothesize that a network similar to the one orchestrated by Pdx1 in the sea urchin neurons was active in an ancestral cell type and then inherited by neuronal and pancreatic developmental lineages in sea urchins and vertebrates.

    1. Developmental Biology

    Visually induced changes in cytokine production in the chick choroid

    Jody A Summers, Elizabeth Martinez
    Research Article Updated

    Postnatal ocular growth is regulated by a vision-dependent mechanism that acts to minimize refractive error through coordinated growth of the ocular tissues. Of great interest is the identification of the chemical signals that control visually guided ocular growth. Here, we provide evidence that the pro-inflammatory cytokine, interleukin-6 (IL-6), may play a pivotal role in the control of ocular growth using a chicken model of myopia. Microarray, real-time RT-qPCR, and ELISA analyses identified IL-6 upregulation in the choroids of chick eyes under two visual conditions that introduce myopic defocus and slow the rate of ocular elongation (recovery from induced myopia and compensation for positive lenses). Intraocular administration of atropine, an agent known to slow ocular elongation, also resulted in an increase in choroidal IL-6 gene expression. Nitric oxide appears to directly or indirectly upregulate choroidal IL-6 gene expression, as administration of the non-specific nitric oxide synthase inhibitor, L-NAME, inhibited choroidal IL-6 gene expression, and application of a nitric oxide donor stimulated IL-6 gene and protein expression in isolated chick choroids. Considering the pleiotropic nature of IL-6 and its involvement in many biological processes, these results suggest that IL-6 may mediate many aspects of the choroidal response in the control of ocular growth.

    1. Developmental Biology
    2. Genetics and Genomics

    Paths and pathways that generate cell-type heterogeneity and developmental progression in hematopoiesis

    Juliet R Girard et al.
    Research Article Updated

    Mechanistic studies of Drosophila lymph gland hematopoiesis are limited by the availability of cell-type-specific markers. Using a combination of bulk RNA-Seq of FACS-sorted cells, single-cell RNA-Seq, and genetic dissection, we identify new blood cell subpopulations along a developmental trajectory with multiple paths to mature cell types. This provides functional insights into key developmental processes and signaling pathways. We highlight metabolism as a driver of development, show that graded Pointed expression allows distinct roles in successive developmental steps, and that mature crystal cells specifically express an alternate isoform of Hypoxia-inducible factor (Hif/Sima). Mechanistically, the Musashi-regulated protein Numb facilitates Sima-dependent non-canonical, and inhibits canonical, Notch signaling. Broadly, we find that prior to making a fate choice, a progenitor selects between alternative, biologically relevant, transitory states allowing smooth transitions reflective of combinatorial expressions rather than stepwise binary decisions. Increasingly, this view is gaining support in mammalian hematopoiesis.