SMN controls neuromuscular junction integrity through U7 snRNP.

The neuromuscular junction (NMJ) is an essential synapse whose loss is a key hallmark of the neurodegenerative disease spinal muscular atrophy (SMA). Here, we show that activity of the SMA-determining SMN protein in the assembly of U7 small nuclear ribonucleoprotein (snRNP)—which functions in the 3′-end processing of replication-dependent histone mRNAs—is required for NMJ integrity. Co-expression of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional abnormalities of neuromuscular pathology in SMA mice—including NMJ denervation, decreased synaptic transmission, and skeletal muscle atrophy. Furthermore, U7 snRNP dysfunction drives selective loss of the synaptic organizing protein Agrin at NMJs innervating vulnerable muscles of SMA mice. These findings reveal a direct contribution of U7 snRNP dysfunction to neuromuscular pathology in SMA and suggest a role for histone gene regulation in maintaining functional synaptic connections between motor neurons and muscles. [Display omitted] • Lsm10 and Lsm11 co-expression enhances U7 snRNP assembly • Selective correction of histone gene dysregulation by Lsm10/11 in SMA models • U7 snRNP dysfunction contributes to neuromuscular pathology in SMA mice • SMN regulates Agrin expression at the NMJ through U7 snRNP NMJ denervation is a hallmark of SMA. Through selective restoration of U7 snRNP biogenesis in SMA mice, Tisdale et al. reveal a role for SMN-mediated U7 snRNP assembly and histone mRNA processing in controlling NMJ integrity through Agrin expression, uncovering RNA-mediated disease mechanisms and linking U7 function to neuromuscular development. [ABSTRACT FROM AUTHOR]