Coordinated cadherin functions sculpt respiratory motor circuit connectivity

Breathing, and the motor circuits that control it, is 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 contract...

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Bibliographic Details
Published in:eLife 2022-12, Vol.11
Main Authors: Vagnozzi, Alicia N, Moore, Matthew T, Lin, Minshan, Brozost, Elyse M, Kc, Ritesh, Agarwal, Aambar, Schwarz, Lindsay A, Duan, Xin, Zampieri, Niccolò, Landmesser, Lynn T, Philippidou, Polyxeni
Format: Article
Language:English
Subjects:
Analysis
Animals
Cadherins
Cell body
Circuits
Connectivity
Dbx1 protein
Developmental Biology
Diaphragm
Firing pattern
Homeodomain Proteins - metabolism
Identification and classification
Interneurons
Interneurons - physiology
Lethality
Mice
Morphology
Motor neurons
Motor Neurons - physiology
Motor task performance
Muscle contraction
N-Cadherin
Neural networks
Neurogenesis
Neuroscience
phrenic motor neurons
Phrenic Nerve
Properties
Respiration
respiratory circuits
Respiratory failure
Respiratory Rate
rVRG
Spinal cord
Topography
Ventilation
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Summary:Breathing, and the motor circuits that control it, is 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 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/ELIFE.82116