Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biology, Life Sciences & Biomedicine - Other Topics, MATRIX METALLOPROTEINASES, AXON GUIDANCE, NEURAL DEVELOPMENT, MOUSE DEVELOPMENT, DISTINCT ROLES, PITX2 ISOFORMS, PHRENIC-NERVE, DIFFERENTIATION, EXPRESSION, NEURONS, Nodal, Slit/Robo, axon guidance, developmental biology, diaphragm, left/right asymmetry, motoneuron, mouse, neuroscience, stem cells, Animals, Animals, Genetically Modified, Diaphragm, Gene Expression Profiling, Mice, Motor Neurons, Neural Pathways, Nodal Protein, Phrenic Nerve, Signal Transduction, 0601 Biochemistry and Cell Biology, 31 Biological sciences, 32 Biomedical and clinical sciences, 42 Health sciences

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.