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

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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.

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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.
Arun Padmanabhan

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Eric D de Groh

Medpace Inc., Cincinnati, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.
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.

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.

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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.