Regulation of phosphoinositide metabolism and calcium dynamics in the neocortex

新皮质中磷酸肌醇代谢和钙动态的调节

• 批准号: 10635365
• 负责人: Eamonn James Dickson
• 金额: $ 41.81万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635365
• 关键词: Address; Affect; Area; Biochemical; Biology; Brain; Calcium; Cell Polarity; Cell membrane; Central Nervous System; Cognition; Complex; Core Protein; Cullin 5 Protein; Data; Development; Embryonic Development; Ensure; Epilepsy; Etiology; Event; Frequencies; Goals; Health; Human; Image; Intellectual functioning disability; Interneurons; Knockout Mice; Knowledge; Language; Lipids; Metabolism; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Multiprotein Complexes; Neocortex; Nervous System; Neuroanatomy; Neuronal Migration Disorder; Neurons; Pathway interactions; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Positioning Attribute; Process; Proteins; Regulation; Reporting; Role; Schizophrenia; Series; Signal Pathway; Signal Transduction; Stereotyping; Stimulus; Structure; Surface; Synapses; Telencephalon; Testing; Therapeutic Intervention; autism spectrum disorder; brain morphology; conditional knockout; excitatory neuron; experimental study; hippocampal pyramidal neuron; inhibitory neuron; lateral ventricle; lissencephaly; loss of function; malformation; migration; mutant; neocortical; nerve stem cell; nervous system development; neural circuit; neuronal excitability; neuropsychiatric disorder; novel; phosphatidylinositol 3,4,5-triphosphate; phosphatidylinositol 4-phosphate; postmitotic; recruit; response; superresolution microscopy; targeted treatment; ubiquitin-protein ligase; voltage

Project Summary/Abstract: The neocortex is an exclusive structure of the mammalian central nervous system. In humans, the neocortex is involved in higher-order brain functions such as cognition and language. All projection neurons in the neocortex are born from a common pool of neural progenitors at the surface of the lateral ventricles of the telencephalon. Post-mitotic projection neurons must migrate from the proliferative niche to their intended cortical layers in order to mature and establish functional synaptic contacts. Misregulation of PN migration has devastating consequences for human health and results in a series of neuronal migration disorders that disrupt neural circuitry and/or brain morphology, leading to cognition problems, neuropsychiatric disease, epilepsy, and neuroanatomical malformations. The overarching goal of this project is to define novel molecular mechanisms that instruct projection neuron migration, migration ending, and settling in their final position in the neocortex. Recently, we have identified the E3 ubiquitin ligase CRL5 as a key regulator of migration and final positioning of projection neurons in the cortex. Here, we aim to understand the CRL5-dependent molecular mechanisms that control pyramidal neuron migration and termination. Our preliminary data indicate that CRL5 regulates the levels of two crucial phosphoinositide signaling lipids, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) in projection neurons. Our data also suggests that CRL5 regulates PIP2 and PIP3 levels by opposing the activity of the phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and phosphoinositide 3-kinases (PI3K), which synthesizes PIP2 and PIP3, respectively. Moreover, CRL5 also controls Ca2+ dynamics by regulating the frequency of Ca2+ events, which are crucial for pyramidal neuron migration. This proposal aims to address the role of CRL5 during projection neuron migration and cortical development by answering the following questions: 1) How does CRL5 regulate PIP5K and PI3K activity to control phosphoinositide levels?, 2) Is CRL5 regulating PIP2 and PIP3 levels to control projection neuron migration?, 3) Does CRL5 participate in Ca2+ dynamics in projection neurons by controlling Ca2+ channels activity/localization?, and 4) Does CRL5-dependent regulation of PIP2 and PIP3 levels directly affect Ca2+ dynamics? The successful completion of the project will provide the first detailed molecular framework of how CRL5 controls projection neuron migration and termination to orchestrate cortical morphogenesis and identify CRL5 as a novel regulator of phosphoinositides metabolism and Ca2+ dynamics in the nervous system. Completion of this project will offering potential targets for therapeutic intervention in neuronal migration disorders.

项目摘要/摘要： 新皮层是哺乳动物中枢神经系统的独特结构。在人类中，新皮层是 参与高阶大脑功能，例如认知和语言。新皮层中的所有投射神经元 来自尾脑侧心室表面的一个普通神经祖细胞池。 有丝分裂后的投射神经元必须按顺序从增殖的生态位迁移到其预期的皮质层 成熟并建立功能性突触接触。 PN迁移的不正调有毁灭性的 对人类健康的后果，导致一系列神经元素疾病破坏神经 电路和/或脑形态，导致认知问题，神经精神疾病，癫痫和 神经解剖畸形。该项目的总体目标是定义新颖的分子机制 该指示投影神经元迁移，迁移结束并定居在新皮层中的最终位置。 最近，我们确定E3泛素连接酶CRL5是迁移和最终定位的关键调节器 皮质中的投射神经元。在这里，我们旨在了解CRL5依赖的分子机制 控制锥体神经元迁移和终止。我们的初步数据表明CRL5调节水平 两个至关重要的磷酸肌醇信号脂质的脂质，磷脂酰肌醇4,5-双磷酸（PIP2）和 投射神经元中的磷脂酰肌醇3,4,5-三磷酸（PIP3）。我们的数据还表明CRL5 通过反对磷脂酰肌醇4-磷酸5-激酶（PIP5K）的活性来调节PIP2和PIP3水平 分别合成PIP2和PIP3的磷酸肌醇3-激酶（PI3K）。而且，CRL5也是如此 通过调节Ca2+事件的频率来控制Ca2+动力学，这对于锥体神经元至关重要 迁移。该建议旨在解决CRL5在投射神经元迁移和皮质中的作用 通过回答以下问题来开发： 1）CRL5如何调节PIP5K和PI3K活性以控制磷酸肌醇水平？2）CRL5是否在调节CRL5 PIP2和PIP3级别以控制投影神经元迁移？3）CRL5是否参与Ca2+动力学 通过控制Ca2+通道活动/本地化的投影神经元？4）CRL5依赖性调节是否是否依赖 PIP2和PIP3水平直接影响Ca2+动力学？该项目的成功完成将提供 CRL5如何控制投影神经元迁移和终止的第一个详细分子框架 编排皮质形态发生，并识别CRL5是磷酸肌醇代谢和的新型调节剂 神经系统中的CA2+动力学。该项目的完成将为治疗提供潜在的目标 干预神经元迁移障碍。