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.
Highlights
The diaphragm is the main respiratory muscle of mammalian organisms, separating the thoracic and abdominal cavities
We further found that the L/R distribution of acetylcholine receptor (AchR) clusters at the nascent neuromuscular junctions differed, with a 2.1 ± 0.2-fold increase in the medio-lateral scattering of AchR clusters on the right side of the diaphragm compared to the left side (N = 11, p
This difference was absent in motoneuron cultures prepared from Rfx3–/– embryos with phenotypic left isomerism (Figure 5D). These results provide evidence that the differential L/R MMP activity is controlled by the Nodal pathway and further suggest that MMP2 contributes to the establishment of phrenic nerve asymmetry
Summary
The diaphragm is the main respiratory muscle of mammalian organisms, separating the thoracic and abdominal cavities. Charoy et al studied how the diaphragm develops in mouse embryos This revealed that the left and right phrenic nerves are not symmetrical. The differences between the nerves and muscles on the left and right sides of the diaphragm could explain why some muscle disorders affect only one side of the diaphragm They could explain why congenital hernias caused by abdominal organs pushing through the diaphragm into the chest cavity mostly affect the left side of the diaphragm. Our findings show that both the diaphragm muscle and phrenic nerves have asymmetries, which are established independently of each other during early embryogenesis
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