1. Developmental Biology
  2. Genetics and Genomics
Download icon

Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

  1. Ki-Sun Park
  2. Beenish Rahat
  3. Hyung Chul Lee
  4. Zu-Xi Yu
  5. Jacob Noeker
  6. Apratim Mitra
  7. Connor M Kean
  8. Russell H Knutsen
  9. Danielle Springer
  10. Claudia M Gebert
  11. Beth A Kozel
  12. Karl Pfeifer  Is a corresponding author
  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, United States
  2. National Heart, Lung, and Blood Institute, United States
  3. The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, United States
  4. National Heart Lung and Blood Institute of the National Institutes of Health, United States
Research Article
  • Cited 0
  • Views 514
  • Annotations
Cite this article as: eLife 2021;10:e67250 doi: 10.7554/eLife.67250

Abstract

Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is primarily in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with Mirlet7 microRNAs.

Data availability

Sequencing data are deposited in the NCBI Gene Expression Omnibus (GEO) under series accession number GSE111418.

The following data sets were generated

Article and author information

Author details

  1. Ki-Sun Park

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Beenish Rahat

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Hyung Chul Lee

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zu-Xi Yu

    The Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jacob Noeker

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4344-3114
  6. Apratim Mitra

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Connor M Kean

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Russell H Knutsen

    Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Danielle Springer

    National Heart Lung and Blood Institute, National Heart Lung and Blood Institute of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Claudia M Gebert

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Beth A Kozel

    Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute of the National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Karl Pfeifer

    Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, Bethesda, United States
    For correspondence
    pfeiferk@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0254-682X

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development Division of Intramural Research (ZIAHD001804)

  • Karl Pfeifer

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 animals were handled according to approved institutional animal care and use committee (IACUC) protocols (050 and 063) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Surgery was performed under Avertin anesthesia and every effort was made to minimize suffering.

Reviewing Editor

  1. Benjamin L Prosser, University of Pennsylvania Perelman School of Medicine, United States

Publication history

  1. Received: February 5, 2021
  2. Preprint posted: February 23, 2021 (view preprint)
  3. Accepted: August 4, 2021
  4. Accepted Manuscript published: August 17, 2021 (version 1)
  5. Version of Record published: September 8, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 514
    Page views
  • 82
    Downloads
  • 0
    Citations

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

Further reading

    1. Developmental Biology
    Soyeon Lim et al.
    Research Article

    Retinal progenitor cells (RPCs) divide in limited numbers to generate the cells comprising vertebrate retina. The molecular mechanism that leads RPC to the division limit, however, remains elusive. Here, we find that the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) in an RPC subset by deletion of tuberous sclerosis complex 1 (Tsc1) makes the RPCs arrive at the division limit precociously and produce Müller glia (MG) that degenerate from senescence-associated cell death. We further show the hyperproliferation of Tsc1-deficient RPCs and the degeneration of MG in the mouse retina disappear by concomitant deletion of hypoxia-induced factor 1-a (Hif1a), which induces glycolytic gene expression to support mTORC1-induced RPC proliferation. Collectively, our results suggest that, by having mTORC1 constitutively active, an RPC divides and exhausts mitotic capacity faster than neighboring RPCs, and thus produces retinal cells that degenerate with aging-related changes.

    1. Developmental Biology
    2. Neuroscience
    Tania Moreno-Mármol et al.
    Research Article Updated

    The vertebrate eye primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby matching the retinal curvature and promoting OV folding. Localized interference with the RPE cytoskeleton disrupts tissue stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation drives RPE expansion with a much-reduced need of cell flattening.