Figure 1. dVCP mutation-dependent motor neuron and muscle phenotypes in Drosophila.

A. Expression of exogenous wild type dVCP in motor neurons with the driver OK371-GAL4 does not impact viability as assessed by rates of eclosion as adults. In contrast, expression of mutant dVCP (R152H) leads to a high rate of pupal lethality. The flies that do eclose die shortly thereafter. Error bars indicate standard error. B. Expression of mutant dVCP (but not wild type) in motor neurons results in a locomotor defect as assessed by monitoring crawling behavior of 3^rd instar larvae. Error bars indicate standard error. C. Expression of mutant dVCP (but not wild type) in motor neurons results in abnormal NMJ morphology with reduced total bouton numbers. NMJs at muscle 4 were used for all analyses. Error bars indicate standard error. D. The abnormal NMJs in flies expressing mutant dVCP in motor neurons results in a frequent ‘ghost boutons’ in which presynaptic structure lacks appositional postsynaptic structure. Ghost boutons are very rarely observed in control animals or animals expressing wild type dVCP. Error bars indicate standard error. E. Representative images of NMJs from the genotypes indicated. The arrowheads point out ghost boutons in an animal expressing mutant dVCP. F. Hemithoraces stained with phalloidin from control flies (MHC-GAL4) and flies expressing wild type or mutant dVCP in muscle under control of MHC-GAL4 show a mutation-dependent myopathy at 10X, and a disruption of sarcomere architecture at 100X. TEM revealed profound abnormalities in mitochondrial morphology with numerous swollen mitochondria with disrupted cristae. See also Supplemental Figure 1 and 2 for further analysis.