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bioRxiv · 10.1101/2023.11.21.568166

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

Christophers, B.·Leahy, S. N.·Soffar, D.·von Saucken, V.·Broadie, K.·Baylies, M.
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Abstract

Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown Drosophila cofilin (DmCFL) 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 DmCFL 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, DmCFL 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 cofilins roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology. Summary statementCofilin regulates muscle postsynaptic actin organization, structural maintenance, glutamate receptor composition, and neuromuscular junction function in a Drosophila nemaline myopathy disease model.

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Christophers, B., Leahy, S. N., Soffar, D., von Saucken, V., Broadie, K., Baylies, M.. 2023-11-22. Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission. https://doi.org/10.1101/2023.11.21.568166

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