1. Developmental Biology

Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel

  1. Eva Lana-Elola
  2. Sheona Watson-Scales
  3. Amy Slender
  4. Dorota Gibbins
  5. Alexandrine Martineau
  6. Charlotte Douglas
  7. Timothy Mohun
  8. Elizabeth MC Fisher
  9. Victor LJ Tybulewicz  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. UCL Institute of Neurology, United Kingdom
https://doi.org/10.7554/eLife.11614
Share this article
Cite this article
  1. Eva Lana-Elola
  2. Sheona Watson-Scales
  3. Amy Slender
  4. Dorota Gibbins
  5. Alexandrine Martineau
  6. Charlotte Douglas
  7. Timothy Mohun
  8. Elizabeth MC Fisher
  9. Victor LJ Tybulewicz
(2016)
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
eLife 5:e11614.
https://doi.org/10.7554/eLife.11614
  2. Download BibTeX
  3. Download .RIS

Abstract

Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion.

Article and author information

Author details

  1. Eva Lana-Elola

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Sheona Watson-Scales

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Amy Slender

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Dorota Gibbins

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Alexandrine Martineau

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Charlotte Douglas

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Timothy Mohun

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  8. Elizabeth MC Fisher

    Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  9. Victor LJ Tybulewicz

    Mill Hill Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Victor.T@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal work was carried out under a Project Licence granted by the UK Home Office.

Copyright

© 2016, Lana-Elola 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

  • 4,581
    views
  • 745
    downloads
  • 87
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Eva Lana-Elola
  2. Sheona Watson-Scales
  3. Amy Slender
  4. Dorota Gibbins
  5. Alexandrine Martineau
  6. Charlotte Douglas
  7. Timothy Mohun
  8. Elizabeth MC Fisher
  9. Victor LJ Tybulewicz
(2016)
Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel
eLife 5:e11614.
https://doi.org/10.7554/eLife.11614

Share this article

https://doi.org/10.7554/eLife.11614

Categories and tags

Research organism

Further reading

    1. Developmental Biology

    Opposing roles for Bmp signalling during the development of electrosensory lateral line organs

    Alexander S Campbell, Martin Minařík ... Clare VH Baker
    Research Article Updated

    The lateral line system enables fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes, but the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts. This is because the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates opposing roles for Bmp signalling during ampullary organ formation.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine

    Single-cell RNA sequencing of the holothurian regenerating intestine reveals the pluripotency of the coelomic epithelium

    Joshua G Medina-Feliciano, Griselle Valentín-Tirado ... José E Garcia-Arraras
    Research Article

    In holothurians, the regenerative process following evisceration involves the development of a ‘rudiment’ or ‘anlage’ at the injured end of the mesentery. This regenerating anlage plays a pivotal role in the formation of a new intestine. Despite its significance, our understanding of the molecular characteristics inherent to the constituent cells of this structure has remained limited. To address this gap, we employed state-of-the-art scRNA-seq and hybridization chain reaction fluorescent in situ hybridization analyses to discern the distinct cellular populations associated with the regeneration anlage. Through this approach, we successfully identified 13 distinct cell clusters. Among these, two clusters exhibit characteristics consistent with putative mesenchymal cells, while another four show features akin to coelomocyte cell populations. The remaining seven cell clusters collectively form a large group encompassing the coelomic epithelium of the regenerating anlage and mesentery. Within this large group of clusters, we recognized previously documented cell populations such as muscle precursors, neuroepithelial cells, and actively proliferating cells. Strikingly, our analysis provides data for identifying at least four other cellular populations that we define as the precursor cells of the growing anlage. Consequently, our findings strengthen the hypothesis that the coelomic epithelium of the anlage is a pluripotent tissue that gives rise to diverse cell types of the regenerating intestinal organ. Moreover, our results provide the initial view into the transcriptomic analysis of cell populations responsible for the amazing regenerative capabilities of echinoderms.