Regulation and Function of Arc in the Nucleus

原子核中电弧的调节和功能

• 批准号: 7997794
• 负责人: Erica Megan Korb
• 金额: $ 3.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997794
• 关键词: Acute Promyelocytic Leukemia; Affect; Cell Nucleus; Cytoskeletal Proteins; Dendrites; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Knockout Mice; Learning; Light; Maintenance; Memory; Memory Loss; Messenger RNA; Modification; Molecular; Neurons; Nuclear; Nuclear Export; Phase; Process; Proteins; Regulation; Short-Term Memory; Site; Stimulus; Synapses; Synaptic plasticity; Transcript; Transcriptional Regulation; Translating; Translations; Tumor Suppressor Proteins; Work; base; gene repression; long term memory; nervous system disorder; public health relevance; research study; response; synaptic function

DESCRIPTION (provided by applicant): The molecular basis of learning and memory is the modification of neuronal synapses in response to electrical activity, a process termed synaptic plasticity. There are two phases of memory formation. Short-term memory results from modifications of preexisting proteins that change synaptic efficacy, while long-term memory formation requires new gene transcription to stabilize these changes. The activity-regulated cytoskeletal protein Arc is the only protein known to be specifically required for long-term memory formation. In Arc knock- out (KO) mice, short-term learning is not affected, but consolidation and maintenance of memory is lost. Arc is also the only known activity-induced gene for which the mRNA transcript is transported specifically to the site of stimulation. Arc is then locally translated in neuronal dendrites and regulates synaptic strength. This allows it to modify synaptic functions in a way that correlates both temporally and spatially with its inducing stimulus. Interestingly, Arc protein is also highly enriched in the nucleus and activity causes an increase in Arc protein within the nucleus. In the nucleus, Arc associates with promyelocytic leukemia tumor suppressor protein nuclear bodies (PML-NBs), which typically regulate transcription. As long-term memory formation requires transcription and is lost in Arc KO mice, Arc might contribute to transcriptional regulation within the nucleus. This finding, combined with the local translation of Arc at activated synapses, might help to explain how a neuron with thousands of synapses and only one nucleus stores information in a manner that is both synapse-specific and dependent on nuclear processes, such as new gene expression. This proposal aims to determine if the activity-induced Arc localization to the nucleus functions as a mechanism to regulate new gene transcription in long-term memory formation. The proposed experiments will clarify the regulation and function of Arc in the nucleus with the goal of elucidating the molecular basis for the consolidation of new memories. This work will ultimately be important not only in our understanding of the molecular processes behind normal memory storage but also will shed light on the processes that are disrupted in neurological disease that affect memory formation and consolidation. Specific Aim 1: To determine if nuclear Arc regulates total AMPAR levels through transcriptional repression. Specific Aim 2: To determine if Arc increases PML-NBs in an activity-dependent manner as a means of regulating transcription. Specific Aim 3: To elucidate the mechanism of Arc nuclear export. PUBLIC HEALTH RELEVANCE: Memories are formed when neurons change the strength of their connections, yet the underlying mechanisms required for these changes are not fully understood. Elucidating the cellular mechanisms behind memory formation is critical to understanding the memory loss and dysfunction that occurs in neurological diseases. This proposal aims to clarify how neurons for long term memories through investigating the function and regulation of the protein Arc which is required for this process.

描述（由申请人提供）：