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2019 | 79 | Suppl.1 |

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Screen for kinesins critical in mTOR-dependent neuronal development

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INTRODUCTION: The mammalian target of rapamycin (mTOR) has an important role in the maturation of developing neuronal cells. It can be seen in the condition of mTOR hyper-activation, which leads to premature differentiation, uncontrolled overgrowth of the dendritic tree, and elevated cell soma sizes in in vitro cultures. In patients, this phenotype leads to diseases like tuberous sclerosis complex, which results in brain tumors, epilepsy, mental retardation, and autism spectrum disorder. In highly polarized cells like neurons, growth and proper development are highly dependent on proper cellular transport, as cargo must be delivered to distant parts of cells especially dendrites and axon. Dynein-dynactin complex and kinesins are motor proteins that play a crucial role in this process. AIM(S): While recent publications show a dependence between dynein and mTOR stimulated growth, not much is known about the interplay between kinesins and mTOR in this process. METHOD(S): A primary screen for kinesins critically involved in mTOR-dependent neuron outgrowth was performed, with the use of a shRNA library targeting 38 different kinesin heavy chain genes (KIFs), while simultaneously stimulating mTOR by PI3‑kinase pathway. Data was collected by transfecting primary rat neuronal cultures in vitro, and measuring soma size and dendritic tree arborization on images taken five days after the transfection. Based on phenotyping of cells after silencing, 10 KIF genes were selected for further investigation. RESULTS: While in almost all cases, silencing of KIF genes resulted in altered neuron phenotype, this may be due to the importance of kinesins in proper cytoskeleton formation. In some of the genes, however, the phenotype was more similar to wild-type neurons in spite of stimulating the PI3K pathway. CONCLUSIONS: Further experiments with neuronal stem cells differentiation, neuro‑progenitor migration, and biochemical analysis will be performed to investigate the relation of the selected genes to the mTOR pathway

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  • Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, Poland
  • Department of Biology, Utrecht University, Utrecht, Netherlands
  • Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, Poland


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