Drosophila CPEB Orb2A Mediates Memory Independent of Its RNA-Binding Domain

• Published in: Neuron (Cambridge, Mass.) Mass.), 2012-10, Vol.76 (2), p.383-395
• Main Authors: Krüttner, Sebastian, Stepien, Barbara, Noordermeer, Jasprina N., Mommaas, Mieke A., Mechtler, Karl, Dickson, Barry J., Keleman, Krystyna
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Behavior; Biogenic Amines - administration & dosage; Brain - metabolism; Brain - ultrastructure; Cell Line; Chromatography, High Pressure Liquid; Courtship; Drosophila; Drosophila Proteins - classification; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Embryo, Nonmammalian; Gene Expression Regulation, Developmental - genetics; Gene targeting; Genotype; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Immunoprecipitation; Insects; Larva; Learning - physiology; Long term memory; Male; Mass Spectrometry; Memory - physiology; Microscopy, Immunoelectron; Mitogen-Activated Protein Kinases - genetics; mRNA Cleavage and Polyadenylation Factors - classification; mRNA Cleavage and Polyadenylation Factors - genetics; mRNA Cleavage and Polyadenylation Factors - metabolism; Mushroom Bodies - cytology; Mushroom Bodies - metabolism; Mutation - genetics; Plasticity (synaptic); Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Structure, Tertiary - physiology; Protein synthesis; Proteins; RNA - genetics; RNA - metabolism; RNA, Messenger - metabolism; RNA-binding protein; RNA-Binding Proteins - physiology; Synapses; Transcription Factors - classification; Transcription Factors - genetics; Transcription Factors - metabolism; Translation
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2012.08.028

Long-term memory and synaptic plasticity are thought to require the synthesis of new proteins at activated synapses. The CPEB family of RNA binding proteins, including Drosophila Orb2, has been implicated in this process. The precise mechanism by which these molecules regulate memory formation is however poorly understood. We used gene targeting and site-specific transgenesis to specifically modify the endogenous orb2 gene in order to investigate its role in long-term memory formation. We show that the Orb2A and Orb2B isoforms, while both essential, have distinct functions in memory formation. These two isoforms have common glutamine-rich and RNA-binding domains, yet Orb2A uniquely requires the former and Orb2B the latter. We further show that Orb2A induces Orb2 complexes in a manner dependent upon both its glutamine-rich region and neuronal activity. We propose that Orb2B acts as a conventional CPEB to regulate transport and/or translation of specific mRNAs, whereas Orb2A acts in an unconventional manner to form stable Orb2 complexes that are essential for memory to persist. ► Orb2A and Orb2B function by distinct mechanisms in long-term memory ► Orb2A function requires its glutamine-rich domain but not its RNA-binding domain ► Orb2B function requires the RNA-binding domain but not its glutamine-rich domain ► Neuronal activation induces Orb2 heteromers dependent upon Orb2A’s glutamine-rich domain RNA binding proteins at synapses may underlie plasticity, but their role is not well understood. Krüttner et al. show here that Orb2 isoforms affect memory by distinct mechanisms: through its RNA-binding domain or by forming heterocomplexes in a manner dependent on its glutamine-rich region and neuronal activity.