NOMeN aims at shedding light on neuromuscular (NM) development from a noncoding RNA (ncRNA) perspective. Focus will be given to tissue-specific ncRNAs that we discovered as players in the proper maturation of the two main cell types (i.e., motoneurons (MNs) and skeletal muscle fibers) which form the neuromuscular junction (NMJ). By applying an experimental design which integrates cellular and molecular approaches, we intend to recapitulate the simultaneous development of nerve and muscle lineages arising from the same pool of progenitor cells through the generation of human NM organoids (NMOs). This system has the unique potential to self-organize with a precise cell positional identity, allowing to study the crosstalk between muscle and nerve counterparts in NM development and NMJ formation. The accuracy of this model will synergize with CRISPR-CAS9 based gene editing and advanced single-cell transcriptomics to provide a cell type-specific picture of the coding and noncoding gene contributions to NM development and enlighten the impact of relevant ncRNAs on cell differentiation or developmental gene pathways. Importantly, the neural or muscle restricted expression of our ncRNA candidates will also allow us to examine non-cell autonomous effects of tissue-specific expression defects. This is crucial for neuromuscular disorders where reciprocal interplay between muscles and nerves is a paradigm (muscle atrophy upon denervation) or a challenge (dying back hypothesis). Over years, our research teams dedicated substantial efforts into the characterization of tissue-specific long ncRNAs (lncRNAs), the most recent class of RNAs increasingly implicated in gene expression regulation. On the “muscular” side, Research Unit 1 has produced important knowledge on pCharme, a muscle-specific, evolutionary conserved lncRNA whose ablation severely impairs skeletal muscle differentiation in both mouse and human. In the nucleus, pCharme acts as an epigenetic regulator by supervising the chromatin localization of MATR3, a multifunctional protein whose mutations were identified in patients affected by myopathies or MN diseases. On the “neuronal” side, Research Unit 2 has identified and described from a molecular and functional point-of-view, the neuronal isoform of HOTAIRM1 (nHM1). nHM1 is required, at the proper developmental stage, for the transition between neuronal precursors and differentiated neurons and it interacts with FUS, an RNA-binding protein whose mutations are associated to amyotrophic lateral sclerosis, a disease characterized by degeneration and death of MNs. On these premises by i) generating physiological NMOs or mutant derivatives lacking the expression of these lncRNAs and ii) by analyzing in these conditions the NMO development, with attention to the structure and the function of the NMJ, our study will provide fresh knowledge to interpret the human NM networks and their impairment upon perturbation of lncRNA homeostasis.