Coordinated cadherin functions sculpt respiratory motor circuit connectivity

  1. Alicia N Vagnozzi
  2. Matthew T Moore
  3. Minshan Lin
  4. Elyse M Brozost
  5. Ritesh KC
  6. Aambar Agarwal
  7. Lindsay A Schwarz
  8. Xin Duan
  9. Niccolò Zampieri
  10. Lynn T Landmesser
  11. Polyxeni Philippidou  Is a corresponding author
  1. Case Western Reserve University, United States
  2. St. Jude Children's Research Hospital, United States
  3. University of California, San Francisco, United States
  4. 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

  1. Alicia N Vagnozzi

    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:" 0000-0002-6152-8728
  2. Matthew T Moore

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

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Elyse M Brozost

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

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Aambar Agarwal

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lindsay A Schwarz

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xin Duan

    Department of Ophthalmology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Niccolò Zampieri

    Max Delbrück Center for Molecular Medicine, 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
  10. Lynn T Landmesser

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. 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 (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.

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.

Reviewing Editor

  1. Anne E West, Duke University, United States

Publication history

  1. Received: July 23, 2022
  2. Accepted: December 29, 2022
  3. Accepted Manuscript published: December 30, 2022 (version 1)

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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  1. Alicia N Vagnozzi
  2. Matthew T Moore
  3. Minshan Lin
  4. Elyse M Brozost
  5. Ritesh KC
  6. Aambar Agarwal
  7. Lindsay A Schwarz
  8. Xin Duan
  9. Niccolò Zampieri
  10. Lynn T Landmesser
  11. Polyxeni Philippidou
(2022)
Coordinated cadherin functions sculpt respiratory motor circuit connectivity
eLife 11:e82116.
https://doi.org/10.7554/eLife.82116

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