Conditional knockout of tumor overexpressed gene in mouse neurons affects RNA granule assembly, granule translation, LTP and short term habituation

• Published in: PloS one 2013-08, Vol.8 (8), p.e69989-e69989
• Main Authors: Barbarese, Elisa, Ifrim, Marius F, Hsieh, Lawrence, Guo, Caiying, Tatavarty, Vedakumar, Maggipinto, Michael J, Korza, George, Tutolo, Jessica W, Giampetruzzi, Anthony, Le, Hien, Ma, Xin-Ming, Levine, Eric, Bishop, Brian, Kim, Duck O, Kuwada, Shigeyuki, Carson, John H
• Format: Article
• Language: English
• Subjects: Animals; Assembly; Autism; Behavior, Animal - physiology; Binding sites; Biology; Brain; Brain slice preparation; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - physiology; Cytoskeleton; Cytoskeleton - metabolism; Dendrites; Excitatory Postsynaptic Potentials - genetics; Female; Gene Knockout Techniques; Genes; Granular materials; Granules; Habituation; Habituation (learning); Habituation, Psychophysiologic - genetics; Hippocampus; House mouse; Hyperactivity; Kinases; Liquid oxygen; Long-term potentiation; Long-Term Potentiation - genetics; Male; Memory; Mice; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - genetics; mRNA; Neurons; Neurons - cytology; Neurons - metabolism; Neurosciences; Potentiation; Protein binding; Protein Biosynthesis - genetics; Proteins; Regulatory sequences; Ribonucleic acid; RNA; RNA - genetics; RNA - metabolism; Rodents; Studies; Synapses - physiology; Synaptic plasticity; Translation; Translation (Genetics); Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069989

In neurons, specific RNAs are assembled into granules, which are translated in dendrites, however the functional consequences of granule assembly are not known. Tumor overexpressed gene (TOG) is a granule-associated protein containing multiple binding sites for heterogeneous nuclear ribonucleoprotein (hnRNP) A2, another granule component that recognizes cis-acting sequences called hnRNP A2 response elements (A2REs) present in several granule RNAs. Translation in granules is sporadic, which is believed to reflect monosomal translation, with occasional bursts, which are believed to reflect polysomal translation. In this study, TOG expression was conditionally knocked out (TOG cKO) in mouse hippocampal neurons using cre/lox technology. In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. In TOG cKO brain slices synaptic sensitivity and long term potentiation (LTP) are reduced. TOG cKO mice exhibit hyperactivity, perseveration and impaired short term habituation. These results suggest that in hippocampal neurons TOG is required for granule assembly, granule translation and synaptic plasticity, and affects behavior.