Dmm019786 669..677

Childrenundergoingcranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life.Wehavedevelopedamodel of neurotoxicdamage in adultDrosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. Wild-type thirdinstar larvae were irradiated with single doses of γ-radiation, and the percentage that survived to adulthood was determined. Motor function of surviving adults was examined with a climbing assay, and longevity wasassessedbymeasuring lifespan.Neuronal cell deathwasassayed by using immunohistochemistry in adult brains. We also tested the sensitivity at different developmental stages by irradiating larvae at various time points. Irradiating late third-instar larvae at a dose of 20 Gy or higher impaired themotor activity of surviving adults. A doseof 40 Gy or higher resulted in a precipitous reduction in the percentage of larvae that survive toadulthood.Adose-dependent decrease inadult longevity was paralleled by a dose-dependent increase in activated Death caspase-1 (Dcp1) in adult brains. Survival to adulthood and adult lifespan were more severely impaired with decreasing larval age at the time of irradiation. Our initial survey of the Drosophila Genetic Reference Panel demonstrated that differences in genotype can confer phenotypic differences in radio-sensitivity for developmental survival and motor function. This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, andhas the potential to unravel underlyingmechanismsand to facilitate the discovery of novel therapeutic interventions.