A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree

  1. Marta Losa
  2. Victor Latorre
  3. Munazah Andrabi
  4. Franck Ladam
  5. Charles Sagerström
  6. Ana Novoa
  7. Peyman Zarrineh
  8. Laure Bridoux
  9. Neil A Hanley
  10. Moises Mallo  Is a corresponding author
  11. Nicoletta Bobola  Is a corresponding author
  1. University of Manchester, United Kingdom
  2. University of Massachusetts Medical School, United States
  3. Instituto Gulbenkian de Ciência, Portugal

Abstract

Connection of the heart to the systemic circulation is a critical developmental event that requires selective preservation of embryonic vessels (aortic arches). However, why some aortic arches regress while others are incorporated into the mature aortic tree remains unclear. By microdissection and deep sequencing in mouse, we find that neural crest (NC) only differentiates into vascular smooth muscle cells (SMCs) around those aortic arches destined for survival and reorganization, and identify the transcription factor Gata6 as a crucial regulator of this process. Gata6 is expressed in SMCs and its target genes activation control SMC differentiation. Furthermore, Gata6 is sufficient to promote SMCs differentiation in vivo, and drive preservation of aortic arches that ought to regress. These findings identify Gata6-directed differentiation of NC to SMCs as an essential mechanism that specifies the aortic tree, and provide a new framework for how mutations in GATA6 lead to congenital heart disorders in humans.

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Article and author information

Author details

  1. Marta Losa

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Victor Latorre

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Munazah Andrabi

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Franck Ladam

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Charles Sagerström

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1509-5810
  6. Ana Novoa

    Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  7. Peyman Zarrineh

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Laure Bridoux

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Neil A Hanley

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3234-4038
  10. Moises Mallo

    Instituto Gulbenkian de Ciência, Oeiras, Portugal
    For correspondence
    mallo@igc.gulbenkian.pt
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9744-0912
  11. Nicoletta Bobola

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    For correspondence
    nicoletta.bobola@manchester.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7103-4932

Funding

Medical Research Council (MR/L009986/1)

  • Nicoletta Bobola

Biotechnology and Biological Sciences Research Council (BB/N00907X/1)

  • Nicoletta Bobola

National Institute of Neurological Disorders and Stroke (NS038183)

  • Charles Sagerström

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

Ethics

Animal experimentation: Experiments on animals followed the local (ASPA 1986, UK; Portaria 1005/92 and Directive 2010/63/EU, P) legislations concerning housing, husbandry, and welfare.

Reviewing Editor

  1. Marianne Bronner, California Institute of Technology, United States

Publication history

  1. Received: August 18, 2017
  2. Accepted: September 25, 2017
  3. Accepted Manuscript published: September 27, 2017 (version 1)
  4. Version of Record published: October 6, 2017 (version 2)

Copyright

© 2017, Losa 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. Marta Losa
  2. Victor Latorre
  3. Munazah Andrabi
  4. Franck Ladam
  5. Charles Sagerström
  6. Ana Novoa
  7. Peyman Zarrineh
  8. Laure Bridoux
  9. Neil A Hanley
  10. Moises Mallo
  11. Nicoletta Bobola
(2017)
A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree
eLife 6:e31362.
https://doi.org/10.7554/eLife.31362

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