Mário Gomes-Pereira

Aims Myotonic dystrophy type I (DM1) is one of the most frequent muscular dystrophies in adults. Although DM1 has long been considered mainly a muscle disorder, growing evidence suggests the involvement of peripheral nerves in the pathogenicity of DM1 raising the question of whether motoneurons (MNs) actively contribute to neuromuscular defects in DM1. Methods By using micropatterned 96‐well plates as a coculture platform, we generated a functional neuromuscular model combining DM1 and muscleblind protein ( MBNL ) knock‐out human‐induced pluripotent stem cells‐derived MNs and human healthy skeletal muscle cells. Results This approach led to the identification of presynaptic defects which affect the formation or stability of the neuromuscular junction at an early developmental stage. These neuropathological defects could be reproduced by the loss of RNA‐binding MBNL proteins, whose loss of function in vivo is associated with muscular defects associated with DM1. These experiments indicate that the functional defects associated with MNs can be directly attributed to MBNL family proteins. Comparative transcriptomic analyses also revealed specific neuronal‐related processes regulated by these proteins that are commonly misregulated in DM1. Conclusions Beyond the application to DM1, our approach to generating a robust and reliable human neuromuscular system should facilitate disease modelling studies and drug screening assays.