Phrenic-specific transcriptional programs shape respiratory motor output
- Case Western Reserve University, United States
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany
- 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
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Gene expression changes in cervical motor neuron transcriptomes after loss of Hox5 transcription factorsNCBI Gene Expression Omnibus, GSE138085.
Article and author information
Author details
Polyxeni Philippidou
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.
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).
Reviewing Editor
- Anne E West, Duke University School of Medicine, United States
Version history
- Received: October 18, 2019
- Accepted: January 14, 2020
- Accepted Manuscript published: January 16, 2020 (version 1)
- 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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Phrenic-specific transcriptional programs shape respiratory motor output
eLife 9:e52859.
https://doi.org/10.7554/eLife.52859
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