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独特结构。在人类中，新皮质是 参与认知和语言等高级大脑功能。新皮质中的所有投射神经元 是由端脑侧脑室表面的共同神经祖细胞池产生的。 有丝分裂后投射神经元必须从增殖生态位迁移到其预期的皮质层，以便 成熟并建立功能性突触接触。对 PN 移民的不当监管造成了毁灭性的后果 对人类健康造成影响并导致一系列神经元迁移障碍，从而破坏神经 电路和/或大脑形态，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的分子机制 指示投射神经元迁移、迁移结束以及在新皮质中的最终位置定居。 最近，我们发现 E3 泛素连接酶 CRL5 是迁移和最终定位的关键调节因子。 皮层中的投射神经元。在这里，我们的目标是了解 CRL5 依赖性分子机制 控制锥体神经元的迁移和终止。我们的初步数据表明 CRL5 调节水平 两种重要的磷酸肌醇信号脂质，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 水平 和磷酸肌醇 3-激酶 (PI3K)，分别合成 PIP2 和 PIP3。此外，CRL5还 通过调节 Ca2+ 事件的频率来控制 Ca2+ 动态，这对于锥体神经元至关重要 迁移。该提案旨在解决 CRL5 在投射神经元迁移和皮质神经元迁移过程中的作用 通过回答以下问题来进行开发： 1) CRL5 如何调节 PIP5K 和 PI3K 活性来控制磷酸肌醇水平？, 2) CRL5 是否调节 PIP2 和 PIP3 水平控制投射神经元迁移？, 3) CRL5 是否参与 Ca2+ 动力学 通过控制 Ca2+ 通道活动/定位来投射神经元？和 4) CRL5 依赖性调节是否有效？ PIP2 和 PIP3 水平直接影响 Ca2+ 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分子框架 协调皮质形态发生并确定 CRL5 作为磷酸肌醇代谢的新型调节剂 神经系统中的 Ca2+ 动态。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。