1. Developmental Biology
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Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis

  1. Neus Martínez-Abadías  Is a corresponding author
  2. Roger Mateu Estivill
  3. Jaume Sastre Tomas
  4. Susan Motch Perrine
  5. Melissa Yoon
  6. Alex Robert-Moreno
  7. Jim Swoger
  8. Lucia Russo
  9. Kazuhiko Kawasaki
  10. Joan Richtsmeier
  11. James Sharpe  Is a corresponding author
  1. The Barcelona Institute for Science and Technology, Spain
  2. Universitat de Barcelona, Spain
  3. Universitat de les Illes Balears, Spain
  4. Pennsylvania State University, United States
Research Article
  • Cited 2
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Cite this article as: eLife 2018;7:e36405 doi: 10.7554/eLife.36405

Abstract

The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying geometric morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously. We identified subtle but significant differences in the gene expression of a downstream target of the Fgfr2 mutation that were associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our method can be applied to different organ systems and models to investigate the etiology of malformations.

Article and author information

Author details

  1. Neus Martínez-Abadías

    Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain
    For correspondence
    nieves.martinez@embl.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3061-2123
  2. Roger Mateu Estivill

    Universitat de Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4728-2239
  3. Jaume Sastre Tomas

    Universitat de les Illes Balears, Palma de Mallorca, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9053-2390
  4. Susan Motch Perrine

    Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Melissa Yoon

    Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alex Robert-Moreno

    Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9042-1316
  7. Jim Swoger

    Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3805-0073
  8. Lucia Russo

    Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Kazuhiko Kawasaki

    Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joan Richtsmeier

    Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. James Sharpe

    Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain
    For correspondence
    james.sharpe@crg.eu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1434-9743

Funding

European Commission (FP7‐PEOPLE‐2012‐ 597 IIF 327382)

  • Neus Martínez-Abadías

National Institute for Health Research (NICHD P01HD078233)

  • Joan Richtsmeier

National Institute for Health Research (NIDCR R01DE02298)

  • Joan Richtsmeier

Burroughs Wellcome Fund (2013 Collaborative Research Travel Grant)

  • Joan Richtsmeier

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 the experiments were performed in compliance with the animal welfare guidelines approved by the Pennsylvania State University Animal Care and Use Committees (IACUC46558, IBC46590).

Reviewing Editor

  1. Clifford J Rosen, Maine Medical Center Research Institute, United States

Publication history

  1. Received: March 21, 2018
  2. Accepted: September 9, 2018
  3. Accepted Manuscript published: September 20, 2018 (version 1)
  4. Version of Record published: October 23, 2018 (version 2)

Copyright

© 2018, Martínez-Abadías 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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