Transcriptome Analysis in a Drosophila Model of Spinal Muscular Atrophy Model Identifies Conserved Genes Required in Muscle for Neuromuscular Junction Architecture.

Using the Drosophila neuromuscular junction (NMJ) as a model, we combined tissue-specific Smn depletion with transcriptomic profiling and prior genetic modifier screens to identify SMN-dependent genes that contribute to postsynaptic architecture.

RNA sequencing revealed numerous transcripts with altered expression or exon usage in Smn-deficient muscle, consistent with SMN’s role in mRNA processing. Functional analysis of selected candidates uncovered novel genes whose muscle-specific knockdown phenocopied Smn loss-of-function, including Actn, Trio, Shroom, and FER, all genes involved in actin cytoskeletal regulation and NMJ maturation. Notably, FER appears to act via the JNK pathway and may be regulated by receptor tyrosine kinases (RTKs), with evidence suggesting muscle-specific SMN sensitivity across RTK signaling pathways.