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

• Main Authors: Camille Charoy, Sarah Dinvaut, Yohan Chaix, Laurette Morlé, Isabelle Sanyas, Muriel Bozon, Karine Kindbeiter, Bénédicte Durand, Jennifer M Skidmore, Lies De Groef, Motoaki Seki, Lieve Moons, Christiana Ruhrberg, James F Martin, Donna M Martin, Julien Falk, Valerie Castellani
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2017-06-01
• Series: eLife
• Subjects: left/right asymmetry; motoneuron; diaphragm; Nodal; Slit/Robo; axon guidance
• Online Access: https://elifesciences.org/articles/18481

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.