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.
- Polyxeni Philippidou
- Polyxeni Philippidou
- Alicia N Vagnozzi
- Alicia N Vagnozzi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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).
- Anne E West, Duke University School of Medicine, United States
© 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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