Regulation of hippocampal morphogenesis and homeostasis by the E3 ubiquitin ligase CRL5

E3 泛素连接酶 CRL5 对海马形态发生和稳态的调节

• 批准号: 9923017
• 负责人: Sergi Simo
• 金额: $ 34.34万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923017
• 关键词: Adaptor Signaling Protein; Address; Adolescent; Adult; Affect; Alzheimer' s Disease; Animals; Area; Axon; Binding; Biological; Biology; Brain; Cells; Cessation of life; Cues; Cullin 5 Protein; Cytoplasmic Granules; Data; Defect; Dendrites; Development; Down-Regulation; Enzymes; Epilepsy; Goals; Hippocampus (Brain); Homeostasis; Human; In Vitro; Intellectual functioning disability; Ligase; Location; Mass Spectrum Analysis; Mental Depression; Methods; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Mus; Mutant Strains Mice; Names; Nervous system structure; Neuraxis; Neurons; Pathologic; Phenotype; Play; Portraits; Positioning Attribute; Process; Proteins; Proto-Oncogene Proteins c-fyn; Pyramidal Cells; Regulation; Retina; Ring Finger Domain; Role; Signal Pathway; Signal Transduction; Synapses; System; Testing; Ubiquitin; adult neurogenesis; cell motility; dentate gyrus; differential expression; experimental study; granule cell; hippocampal pyramidal neuron; memory consolidation; migration; mossy fiber; multicatalytic endopeptidase complex; mutant; nerve stem cell; nerve supply; newborn neuron; novel; protein complex; recruit; response; stem cells; ubiquitin-protein ligase; way finding

Project Summary/Abstract: A long-standing question in biology is how cells respond to the myriad of signals around them generating a specific response. A paradigmatic example is found during mammalian brain development. Neurons born from progenitor cells located in discrete niches move out and migrate, sometimes long distances, to reach their final position. A variety of guidance cues pilot these neurons from their birthplace to their final location, where they stop, mature and integrate into the existing cellular network. Signaling pathways are activated in response to guidance cues or chemotactic signals and once the information is transduced, the original signaling pathway must be downregulated. Inappropriate regulation of signaling pathways causes neurons to mismigrate, lose responsiveness to new signals and/or sustain the original signaling response, causing harm or death to the cell. The overarching goal of the present project is to understand the mechanisms by which ubiquitin- dependent degradation of specific substrate proteins regulates hippocampal development and adult neurogenesis. The ubiquitin-proteasome system is one of the most efficient methods to tightly control signaling pathways, by targeting key signaling components for degradation. This system relies on the coordinated action of 3 enzymes, named E1, E2 and E3 ligases to conjugate the small protein ubiquitin to specific signaling effectors that will be targeted for degradation. The PI previously identified the E3 Cullin-5 RING ligase (CRL5) as a crucial regulator of neuron migration and cell position in several areas of the nervous system. However, the role of CRL5 in the developing and adult hippocampus has never been investigated. Our preliminary data identified novel CRL5-regulated signaling effectors during hippocampal development. Also, we show that CRL5 regulates the position of pyramidal neurons in the CA and neural progenitors and granule cells in the dentate gyrus. Moreover, depletion of CRL5 activity disrupts dendritogenesis and axogenesis of hippocampal neurons. Finally, our preliminary data also indicates that CRL5 regulates adult neurogenesis in the dentate gyrus. The three proposed specific aims will significantly advance our understanding of the role of CRL5 in the developing and adult hippocampus by answering: 1) Which signaling pathways are regulated by CRL5 in the developing hippocampus and in the adult?; 2) What is the role of the ARLA4C signaling in the hippocampus?; 3) How does CRL5 regulate migration and dendrite and axon formation in hippocampal cells?; and 4) How does CRL5 influence adult neurogenesis? The successful completion of the project will provide the first molecular portrait of the hippocampal signaling pathways regulated by CRL5, reveal the biological role of CRL5 in the hippocampus, and identify CRL5 as a novel regulator of adult neurogenesis in the hippocampus.

项目摘要/摘要： 生物学上的一个长期存在的问题是细胞如何响应周围的无数信号产生 具体响应。在哺乳动物脑发育过程中发现了一个范式的例子。神经元从 位于离散壁ni的祖细胞移出并迁移，有时是长距离，以达到最终 位置。从出生地到最终位置的各种指导提示这些神经元的飞行员 停止，成熟并集成到现有的蜂窝网络中。信号通路被激活 引导提示或趋化信号，一旦传输信息，原始信号通路 必须下调。信号通路的不当调节会导致神经元失去神经元，损失 对新信号的响应和/或维持原始信号响应，造成伤害或死亡 细胞。本项目的总体目标是了解泛素的机制 特定底物蛋白的依赖性降解可调节海马发育和成人 神经发生。泛素 - 蛋白酶体系统是严格控制信号的最有效方法之一 途径，通过靶向降解的键信号成分。该系统依赖于协调的动作 3种酶，称为E1，E2和E3连接酶，将小蛋白泛素结合到特定的信号传导 将针对降解的效应子。 PI先前鉴定出E3 Cullin-5环连接酶（CRL5） 作为神经元迁移和细胞位置的关键调节剂在神经系统的多个区域中。然而， CRL5在发展中国家和成人海马中的作用从未被研究过。我们的初步数据 在海马发育过程中确定了新型CRL5调节的信号传导效应子。另外，我们证明CRL5 调节锥体神经元在Ca和神经祖细胞和颗粒细胞中的位置 回。此外，CRL5活性的耗竭会破坏海马神经元的树突生成和轴发生。 最后，我们的初步数据还表明CRL5调节齿状回中的成年神经发生。这 提出的三个特定目标将大大提高我们对CRL5在发展中的作用的理解 通过回答：1）在发育中的CRL5调节哪些信号通路 海马和成年人？ 2）ARLA4C信号在海马中的作用是什么？ 3）如何 CRL5是否调节海马细胞中的迁移，树突和轴突形成？ 4）CRL5如何 影响成人神经发生？该项目的成功完成将提供第一个分子肖像 由CRL5调节的海马信号通路，揭示了CRL5在 海马，并将CRL5识别为海马中成人神经发生的新调节剂。