Sidestep-induced neuromuscular miswiring causes severe locomotion defects in Drosophila larvae

Abstract

Mutations in motor axon guidance molecules cause aberrant projection patterns of motor nerves. As most studies in have analysed these molecules in fixed embryos, the consequences for larval locomotion are entirely unexplored Here, we took advantage of ()-mutant larvae that display severe locomotion defects because of irreparable innervation errors. Mutations in affected all motor nerve branches and all body wall regions. Innervation defects were non-stereotypical, showing unique innervation patterns in each hemisegment. Premature activation of Side in muscle precursors abrogated dorsal migration of motor nerves, resulting in larvae with a complete loss of neuromuscular junctions on dorsal-most muscles. High-speed videography showed that these larvae failed to maintain substrate contact and inappropriately raised both head and tail segments above the substrate, resulting in unique 'arching' and 'lifting' phenotypes. These results show that guidance errors in mutants are maintained throughout larval life and are asymmetrical with respect to the bilateral body axis. Together with similar findings in mice, this study also suggests that miswiring could be an underlying cause of inherited movement disorders.

Parkin expression reverses mitochondrial dysfunction in fused in sarcoma‐induced amyotrophic lateral sclerosis

“…B). A recent study showed that a larval motor exon defect caused unbalanced locomotion including ‘arching’ and ‘lifting’ phenotypes (Kinold et al ., ). This finding might help to better understand the FUS‐induced paralytic defect in Drosophila .…”

Transsynaptic interactions between IgSF proteins DIP-α and Dpr10 are required for motor neuron targeting specificity

“…A number of mutant screens for alterations in the morphologies and patterning of NMJs in the larval neuromuscular system have been performed (Aberle et al, 2002; Kraut et al, 2001; Valakh et al, 2012). LOF mutations in a few genes, including those encoding the cell-surface IgSF domain protein Sidestep and its binding partner, Beaten Path, cause motor axons to fail to arborize normally onto any muscle fibers, resulting in large-scale alterations in innervation patterns (Kinold et al, 2018; Pipes et al, 2001; Siebert et al, 2009; Sink et al, 2001). However, there are no prior reports (to our knowledge) of LOF mutations in single genes that cause high-penetrance changes in targeting of single larval motor axons to individual, or groups of, muscle fibers.…”

Axon Guidance and Collective Cell Migration by Substrate-Derived Attractants

“…Drosophila peripheral nerves express several axon guidance receptors of the immunoglobulin superfamily, but in direct comparisons, Side seems to be most potent in attracting motor axons (Kinold et al, 2018). In fact, overexpression of Side, but not the homophilic adhesion proteins Fasciclin II or Neuroglian, in developing muscles irreversibly attracted dorsally-directed ISN motor axons to ventral and lateral muscle precursors (Kinold et al, 2018).…”

“…Drosophila peripheral nerves express several axon guidance receptors of the immunoglobulin superfamily, but in direct comparisons, Side seems to be most potent in attracting motor axons (Kinold et al, 2018). In fact, overexpression of Side, but not the homophilic adhesion proteins Fasciclin II or Neuroglian, in developing muscles irreversibly attracted dorsally-directed ISN motor axons to ventral and lateral muscle precursors (Kinold et al, 2018). The Drosophila genome contains several paralogs of Beat and Side, and recent interactome assays revealed that several family members form ligand-receptor pairs or are expressed in synaptic partner neurons (Özkan et al, 2013; Tan et al, 2015).…”