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： 新皮质是哺乳动物中枢神经系统的专属结构。在人类中，新皮质是 参与更高级的大脑功能，如认知和语言。新皮质内的所有投射神经元 它们来自端脑侧脑室表面的一个共同的神经前体细胞池。 有丝分裂后投射神经元必须从增殖的壁龛有序地迁移到其预定的皮质层 成熟并建立功能性突触联系。对PN迁移的不当调控具有毁灭性 对人类健康的影响，并导致一系列神经元迁移障碍，扰乱神经 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。这个项目的首要目标是定义新的分子机制。 指示投射神经元迁移，迁移结束，并在其在新皮质的最终位置。 最近，我们已经确定E3泛素连接酶CRL5是移行和最终定位的关键调节因子。 大脑皮层的投射神经元。在这里，我们旨在了解CRL5依赖的分子机制 控制锥体神经元的迁移和终止。我们的初步数据表明，CRL5调节这些水平 两种重要的磷脂酰肌醇信号脂，磷脂酰肌醇4，5-二磷酸(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 通过对抗磷脂酰肌醇4-磷酸5-激酶(PIP5K)的活性来调节PIP2和PIP3的水平 和磷脂酰肌醇3-激酶(PI3K)，分别合成PIP2和PIP3。此外，CRL5还 通过调节对锥体神经元至关重要的钙离子事件的频率来控制钙离子动力学 迁移。这项建议旨在解决CRL5在投射神经元迁移和皮质中的作用 通过回答以下问题促进发展： 1)CRL5是如何调节PIP5K和PI3K活性来控制肌醇磷脂水平的？2)CRL5是否在调节 PIP2和PIP3水平控制投射神经元迁移？，3)CRL5参与钙动力学 通过控制钙通道的活动/定位来投射神经元？以及4)CRL5依赖的调节 PIP2和PIP3水平直接影响钙动态？该项目的成功完成将为 CRL5如何控制投射神经元迁移和终止的第一个详细的分子框架 协调皮质形态发生并确认CRL5是一种新的磷脂酰肌醇代谢和调节因子 神经系统中的钙离子动力学。该项目的完成将为治疗提供潜在的靶点 对神经元迁移障碍的干预。