Coordinated cadherin functions sculpt respiratory motor circuit connectivity
- Case Western Reserve University, United States
- St. Jude Children's Research Hospital, United States
- University of California, San Francisco, United States
- Max Delbrück Center for Molecular Medicine, Germany
Abstract
Breathing, and the motor circuits that control it, are essential for life. At the core of respiratory circuits are Dbx1-derived interneurons, which generate the rhythm and pattern of breathing, and phrenic motor neurons (MNs), which provide the final motor output that drives diaphragm muscle contractions during inspiration. Despite their critical function, the principles that dictate how respiratory circuits assemble are unknown. Here we show that coordinated activity of a type I cadherin (N-cadherin) and type II cadherins (Cadherin-6, -9, and -10) is required in both MNs and Dbx1-derived neurons to generate robust respiratory motor output. Both MN- and Dbx1-specific cadherin inactivation in mice during a critical developmental window results in perinatal lethality due to respiratory failure and a striking reduction in phrenic MN bursting activity. This combinatorial cadherin code is required to establish phrenic MN cell body and dendritic topography; surprisingly, however, cell body position appears to be dispensable for the targeting of phrenic MNs by descending respiratory inputs. Our findings demonstrate that type I and type II cadherins function cooperatively throughout the respiratory circuit to generate a robust breathing output and reveal novel strategies that drive the assembly of motor circuits.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 1,2,3,4 and 6.
Article and author information
Author details
Polyxeni Philippidou
Funding
National Institute of Neurological Disorders and Stroke (R01NS114510)
- Polyxeni Philippidou
National Eye Institute (R01EY030138)
- Xin Duan
Eunice Kennedy Shriver National Institute of Child Health and Human Development (F30HD096788)
- Alicia N Vagnozzi
National Institute of Neurological Disorders and Stroke (F31NS124240)
- Matthew T Moore
National Institute of Neurological Disorders and Stroke (F31NS120699)
- Ritesh KC
St. Jude Children's Research Hospital
- Lindsay A Schwarz
NIHGM (T32GM007250)
- Alicia N Vagnozzi
NIHGM (T32GM008056)
- Ritesh KC
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Anne E West, Duke University, United States
Ethics
Animal experimentation: Mouse colony maintenance and handling was performed in compliance with protocols approved by the Institutional Animal Care Use Committee of Case Western Reserve University (assurance number: A-3145-01, protocol number: 2015-0180). Mice were housed in a 12-hour light/dark cycle in cages containing no more than five animals at a time.
Version history
- Received: July 23, 2022
- Preprint posted: August 4, 2022 (view preprint)
- Accepted: December 29, 2022
- Accepted Manuscript published: December 30, 2022 (version 1)
- Version of Record published: February 9, 2023 (version 2)
Copyright
© 2022, 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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Coordinated cadherin functions sculpt respiratory motor circuit connectivity
eLife 11:e82116.
https://doi.org/10.7554/eLife.82116
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