HIF-2α is essential for carotid body development and function

  1. David Macias  Is a corresponding author
  2. Andrew S Cowburn
  3. Hortensia Torres-Torrelo
  4. Patricia Ortega-Sáenz
  5. José López-Barneo
  6. Randall Johnson  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. Instituto de Biomedicina de Sevilla (IBiS), Spain

Abstract

Mammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2α, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body. The loss of these cells renders mice incapable of ventilatory responses to hypoxia, and this has striking effects on processes as diverse as arterial pressure regulation, exercise performance, and glucose homeostasis. We show that the expansion of the glomus cells is correlated with mTORC1 activation, and is functionally inhibited by rapamycin treatment. These findings demonstrate the central role played by HIF-2α in carotid body development, growth and function.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. David Macias

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    dm670@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8676-1964
  2. Andrew S Cowburn

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Hortensia Torres-Torrelo

    Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Patricia Ortega-Sáenz

    Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. José López-Barneo

    Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Randall Johnson

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    rsj33@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4084-6639

Funding

Wellcome

  • Randall Johnson

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 work was carried out with approval and following review of the University of Cambridge AWERB (Animal Welfare Ethical Review Board) and under license of the UK Home Office (Home Office License numbers 80/2618 and PC64B8953).

Copyright

© 2018, Macias 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

  • 2,439
    views
  • 401
    downloads
  • 51
    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. David Macias
  2. Andrew S Cowburn
  3. Hortensia Torres-Torrelo
  4. Patricia Ortega-Sáenz
  5. José López-Barneo
  6. Randall Johnson
(2018)
HIF-2α is essential for carotid body development and function
eLife 7:e34681.
https://doi.org/10.7554/eLife.34681

Share this article

https://doi.org/10.7554/eLife.34681

Further reading

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Olivia B Taylor, Nicholas DeGroff ... Andy J Fischer
    Research Article

    The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.