1. Cell Biology
  2. Developmental Biology

Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos

  1. Amanda D Yzaguirre
  2. Arun Padmanabhan
  3. Eric D de Groh
  4. Kurt A Engleka
  5. Jun Li
  6. Nancy A Speck
  7. Jonathan A Epstein  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Harvard Medical School, United States
  3. Medpace Inc., United States
https://doi.org/10.7554/eLife.07780
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  1. Amanda D Yzaguirre
  2. Arun Padmanabhan
  3. Eric D de Groh
  4. Kurt A Engleka
  5. Jun Li
  6. Nancy A Speck
  7. Jonathan A Epstein
(2015)
Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos
eLife 4:e07780.
https://doi.org/10.7554/eLife.07780
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Abstract

Type I Neurofibromatosis (NF1) is caused by mutations in the NF1 gene encoding neurofibromin. Neurofibromin exhibits Ras GTPase activating protein (Ras-GAP) activity that is thought to mediate cellular functions relevant to disease phenotypes. Loss of murine Nf1 results in embryonic lethality due to heart defects, while mice with monoallelic loss of function mutations, or with tissue-specific inactivation have been used to model NF1. Here, we characterize previously unappreciated phenotypes in Nf1-/- embryos, which are inhibition of hemogenic endothelial specification in the dorsal aorta, enhanced yolk sac hematopoiesis, and exuberant cardiac blood island formation. We show that a missense mutation engineered into the active site of the Ras-GAP domain is sufficient to reproduce ectopic blood island formation, cardiac defects and overgrowth of neural crest-derived structures seen in Nf1-/- embryos. These findings demonstrate a role for Ras-GAP activity in suppressing hemogenic potential of the heart, and restricting growth of neural crest-derived tissues.

Article and author information

Author details

  1. Amanda D Yzaguirre

    Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Arun Padmanabhan

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Eric D de Groh

    Medpace Inc., Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Kurt A Engleka

    Cardiovascular Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jun Li

    Cardiovascular Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Nancy A Speck

    Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Jonathan A Epstein

    Cardiovascular Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, University of Pennsylvania, Philadelphia, United States
    For correspondence
    epsteinj@upenn.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Kevin Shannon, University of California, San Francisco, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations inthe Guide for the Care and Use of Laboratory Animals of the NationalInstitutes of Health. All of the animals were handled according toapproved institutional animal care and use committee (IACUC) protocols(#803789 and #803317) of the University of Pennsylvania.

Version history

  1. Received: March 30, 2015
  2. Accepted: October 12, 2015
  3. Accepted Manuscript published: October 13, 2015 (version 1)
  4. Version of Record published: December 8, 2015 (version 2)

Copyright

© 2015, Yzaguirre 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. Amanda D Yzaguirre
  2. Arun Padmanabhan
  3. Eric D de Groh
  4. Kurt A Engleka
  5. Jun Li
  6. Nancy A Speck
  7. Jonathan A Epstein
(2015)
Loss of neurofibromin Ras-GAP activity enhances the formation of cardiac blood islands in murine embryos
eLife 4:e07780.
https://doi.org/10.7554/eLife.07780

Share this article

https://doi.org/10.7554/eLife.07780

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