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Elife. 2017 Jun 22;6. pii: e18481. doi: 10.7554/eLife.18481.

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation.

Author information

1
University of Lyon, Claude Bernard University Lyon 1, INMG UMR CNRS 5310, INSERM U1217, Lyon, France.
2
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States.
3
Department of Communicable Diseases, University of Michigan Medical Center, Ann Arbor, United States.
4
Animal Physiology and Neurobiology Section, Department of Biology, Laboratory of Neural Circuit Development and Regeneration, Leuven, Belgium.
5
Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
6
UCL Institute of Ophthalmology, University College London, London, United Kingdom.
7
Baylor College of Medicine, Houston, United States.
8
Department of Human Genetics, University of Michigan Medical Center, Ann Arbor, United States.

Abstract

The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. Here, we have combined the analysis of genetically modified mouse models with transcriptomic analysis to show that both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. We further found that phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry.

KEYWORDS:

Nodal; Slit/Robo; axon guidance; developmental biology; diaphragm; left/right asymmetry; motoneuron; mouse; neuroscience; stem cells

PMID:
28639940
PMCID:
PMC5481184
DOI:
10.7554/eLife.18481
[Indexed for MEDLINE]
Free PMC Article

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