biostudies-literatureUnknownChristophers BNICHD NIH HHSNIMH NIH HHSNCI NIH HHSNIAMS NIH HHSNIGMS NIH HHSCofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown <i>Drosophila</i> cofilin (<i>DmCFL</i>) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by <i>DmCFL</i> knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, <i>DmCFL</i> knockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin's roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.bioRxiv : the preprint server for biology2023.11.21.568166https://www.ebi.ac.uk/biostudies/studies/S-EPMC10690168biostudies-literatureMuscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission.PMC10690168T32 GM007739R01 MH084989T32 HD060600P30 CA008748F30 HD111309R01 AR068128Baylies MKChristophers BSoffar DBLeahy SNvon Saucken VEBroadie KfalseMuscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission.Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown <i>Drosophila</i> cofilin (<i>DmCFL</i>) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by <i>DmCFL</i> knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, <i>DmCFL</i> knockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin's roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.2023-01-01T00:00:00Z2023 Nov2025-04-22T11:18:26.051Z2025-04-05T23:50:53.074ZS-EPMC106901683804530610.1101/2023.11.21.568166