Molecular crosstalk between muscles and motor neurons and its role in neuromuscular circuit assembly

Chronic or acute diseases affecting the neuromuscular system can cause debilitating symptoms in human patients, yet they may manifest through very different etiologies. For example, either muscle or nerve tissue can present the primary pathological phenotype. However, the intricate functional connection between the two tissues, through so-called neuromuscular circuits, will eventually result in deficiencies in both, if disease is allowed to progress unchecked. Correct embryonic assembly of these neuromuscular circuits is essential, in order to ensure faithful muscle-nerve communication. The required circuit specificity is determined - at least in part - by molecularly defined subgroups of motor neurons, so-called motor neuron «pools». Neurons of a given pool project their axons to a single muscle in the periphery. Whether or not distinct molecular subtypes also exist among the various muscle groups is currently less clear. We know, however, that both antero- and retrograde signals between muscle fibers and motor neurons play a crucial role in refining these circuits during development, and maintaining robustness and functionality during homeostasis. The goal of this proposal is thus to profile molecular signatures of circuit-specific muscle and motor neuron pairs, and to functionally test their relevance in neuromuscular circuit formation. For this, I propose to combine state-of-the-art single-cell RNA-sequencing of axon-backfilled motor neurons with bulk transcriptomic analyses of micro-dissected limb muscles connected to the corresponding motor neuron pools. Furthermore, we will exploit a unique experimental setting, in which one of the main motor nerve branches is re-routed and ectopically connects to a duplicated muscle, thereby shunting the original circuit logic. We will evaluate the role of emerging candidate genes using gain- and loss-of- function approaches in both muscle- and neuron-lineages. A better understanding of the molecular crosstalk between muscle and motor neurons will provide new insights into the mechanisms of neuromuscular circuit formation, refinement and maintenance, as well as support the development of regenerative therapies for treating human muscle and nerve diseases.