Phrenic-specific transcriptional programs shape respiratory motor output

  1. Alicia N Vagnozzi
  2. Kiran Garg
  3. Carola Dewitz
  4. Matthew T Moore
  5. Jared M Cregg
  6. Lucie Jeannotte
  7. Niccolò Zampieri
  8. Lynn T Landmesser
  9. Polyxeni Philippidou  Is a corresponding author
  1. Case Western Reserve University, United States
  2. Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany
  3. Centre de Recherche sur le Cancer de l'Université Laval, Canada

Abstract

The precise pattern of motor neuron (MN) activation is essential for the execution of motor actions; however, the molecular mechanisms that give rise to specific patterns of MN activity are largely unknown. Phrenic MNs integrate multiple inputs to mediate inspiratory activity during breathing and are constrained to fire in a pattern that drives efficient diaphragm contraction. We show that Hox5 transcription factors shape phrenic MN output by connecting phrenic MNs to inhibitory pre-motor neurons. Hox5 genes establish phrenic MN organization and dendritic topography through the regulation of phrenic-specific cell adhesion programs. In the absence of Hox5 genes, phrenic MN firing becomes asynchronous and erratic due to loss of phrenic MN inhibition. Strikingly, mice lacking Hox5 genes in MNs exhibit abnormal respiratory behavior throughout their lifetime. Our findings support a model where MN-intrinsic transcriptional programs shape the pattern of motor output by orchestrating distinct aspects of MN connectivity.

Data availability

Sequencing data have been deposited in GEO under accession code GSE138085

The following data sets were generated

Article and author information

Author details

  1. Alicia N Vagnozzi

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kiran Garg

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Carola Dewitz

    Diseases of the Nervous System, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew T Moore

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jared M Cregg

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0027-9748
  6. Lucie Jeannotte

    Oncology, Centre de Recherche sur le Cancer de l'Université Laval, Québec, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Niccolò Zampieri

    Diseases of the Nervous System, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2228-9453
  8. Lynn T Landmesser

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Polyxeni Philippidou

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    For correspondence
    pxp282@case.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0733-3591

Funding

National Institute of Neurological Disorders and Stroke (R00NS085037)

  • Polyxeni Philippidou

Mt Sinai Foundation

  • Polyxeni Philippidou

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F30HD096788)

  • Alicia N Vagnozzi

National Institute of General Medical Sciences (T32GM007250)

  • Alicia N Vagnozzi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Ethics

Animal experimentation: All animal procedures performed in this study were in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Case Western Reserve University School of Medicine Institutional Animal Care and Use Committee (Animal Welfare Assurance Number A3145-01, protocol #: 2015-0180).

Version history

  1. Received: October 18, 2019
  2. Accepted: January 14, 2020
  3. Accepted Manuscript published: January 16, 2020 (version 1)
  4. Version of Record published: February 7, 2020 (version 2)

Copyright

© 2020, Vagnozzi 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. Alicia N Vagnozzi
  2. Kiran Garg
  3. Carola Dewitz
  4. Matthew T Moore
  5. Jared M Cregg
  6. Lucie Jeannotte
  7. Niccolò Zampieri
  8. Lynn T Landmesser
  9. Polyxeni Philippidou
(2020)
Phrenic-specific transcriptional programs shape respiratory motor output
eLife 9:e52859.
https://doi.org/10.7554/eLife.52859

Share this article

https://doi.org/10.7554/eLife.52859

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