Exosomal miRNA in neuron to astroglial communication in the CNS

中枢神经系统神经元与星形胶质细胞通讯中的外泌体 miRNA

• 批准号: 10653994
• 负责人: Yongjie Yang
• 金额: $ 42.87万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653994
• 关键词: Address; Adult; Affect; Astrocytes; Biochemical; Biological; Blood Vessels; Brain; Cell Communication; Cells; Cellular biology; Central Nervous System Diseases; Coculture Techniques; Communication; Complement 1q; Cre driver; Data; Development; Diameter; Early Endosome; Endosomes; Exercise; Genetic; Genetic Transcription; Glioblastoma; Glutamate Transporter; Human; Image; Immune; In Situ; In Vitro; Injections; Knowledge; Label; Ligands; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Molecular; Molecular Biology; Monitor; Morphogenesis; Morphology; Motor Neurons; Mus; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; PHluorin; Pathologic; Pathway interactions; Physiology; Process; Publishing; Regulation; Role; Sampling; Signal Transduction; Spinal; Surface; Synapses; Synaptic Transmission; Testing; Vertebral column; Vesicle; Virus; cell type; designer receptors exclusively activated by designer drugs; exosome; extracellular vesicles; fluorescence imaging; genome-wide; in vivo; insight; intercellular communication; mouse genetics; myelination; nervous system disorder; neurotransmitter release; notch protein; novel; receptor; synaptic function; transcriptome

Abstract Neuron to (astro)glia communication is essential for functional synaptic transmission and physiology in the CNS. Despite the important modulatory roles of astroglia in synapse function, molecular pathways that regulate the neuron-astroglia functional unit are largely undefined. Exosomes (50-150 nm in diameter), a major type of secreted extracellular vesicles (EVs), are derived from intraluminal vesicles (ILVs) in the early endosomal compartment and are released from cells during endosome maturation. EVs and exosomes secreted from various CNS cell types have emerged as a novel and important intercellular communication pathway in the CNS. In particular, miRNAs (miRs) are often found in exosomes to shuttle between cells for intercellular signaling. Intercellular transfers of miRs have been observed in CNS cells to regulate glutamate transporter function, promote myelination, and maintain brain vascular integrity. Exosomal signaling has also been implicated in pathological conditions of the CNS, including neurological injury, neurodegenerative diseases, and glioblastoma. Despite the strong rigor in prior studies to suggest the importance of the exosomal pathway in CNS cell communication, these studies are largely based on culture models or human CSF samples, exosome signaling in situ in the CNS remains essentially unexplored. In addition, fundamentally important cell biology aspects of this pathway, such as neuronal activity's influence, exosome internalization mechanisms, and downstream regulation in recipient CNS cells also remain unknown. This is particularly important to address as CNS cell types are highly distinct from cancer/immune cells where most of exosome knowledge is currently gained and exosome signaling mechanisms can be very cell-type heterogeneous. Based on our published study and additional preliminary results, we propose the following aims in this project: Aim 1: Determine the effect of neuronal activity on the subcellular localization of ILVs and neuronal exosome secretion; Aim 2: Dissect recognition pathways and entry mechanisms involved in astroglial internalization of neuronal exosomes; Aim 3: Investigate genetic regulation of neuronal exosomal miR-124 in astroglia; We have generated a large amount of preliminary data to support our rationales and to demonstrate feasibility for proposed aims. We will employ mouse genetics, molecular biology, virus injections, various imaging, and biochemical approaches to complete these aims. Outcomes from this project will present in vivo evidence to support a previously unrecognized mode of communication from neurons to glia in the CNS. It will also provide much-needed cell biological knowledge and insights for understanding exosome signaling in neuron to glia communication, especially about miR-124-3p's non-cell autonomous genetic regulation in astroglia following its internalization. As altered neuron to (astro)glia communication is clearly implicated in many neurological diseases, this knowledge and insights can significantly help understand how this pathway is involved in CNS diseases.

摘要 神经元到星形胶质细胞的通讯对于功能性突触传递和生理学来说是必不可少的。 中枢神经系统。尽管星形胶质细胞在突触功能中起着重要的调节作用，但 调节神经元-星形胶质细胞的功能单位在很大程度上是未知的。外体(直径50-150 nm)，主要 分泌型细胞外小泡(EVS)是由早期内体的管腔内小泡(ILV)衍生而来 在内体成熟的过程中从细胞中释放出来。EV和外周小体由 各种类型的中枢神经系统细胞已成为中枢神经系统中一种新的重要的细胞间通讯途径。 特别是，miRNAs(MiRs)经常存在于外体中，在细胞之间穿梭，进行细胞间信号传递。 已经在中枢神经系统细胞中观察到miRs的细胞间转移来调节谷氨酸转运体的功能， 促进髓鞘形成，保持脑血管完整性。胞外体信号转导也牵涉到 中枢神经系统的病理状态，包括神经损伤、神经退行性疾病和胶质母细胞瘤。 尽管先前的研究表明外体途径在中枢神经系统细胞中的重要性是非常严格的 这些研究主要是基于培养模型或人类脑脊液样本，外显体信号 位于中南半球的原址基本上仍未被勘探。此外，最重要的细胞生物学方面 这一途径，如神经元活动的影响，外切体内化机制，以及下游 受体中枢神经系统细胞的调控也仍然未知。这对于将其称为CNS细胞尤为重要 类型与癌症/免疫细胞高度不同，目前大多数外显体知识都是在癌症/免疫细胞中获得的 外切体信号机制可以是非常细胞类型的异质性。 基于我们已发表的研究和其他初步结果，我们在这方面提出了以下目标 项目：目标1：确定神经元活动对ILV和神经元亚细胞定位的影响 外体分泌；目标2：解剖星形胶质细胞的识别途径和进入机制 神经元外体的内化；目的3：研究神经元外体miR-124的遗传调控 我们已经生成了大量的初步数据来支持我们的理论并证明 拟议目标的可行性。我们将使用小鼠遗传学，分子生物学，病毒注射，各种成像， 和生物化学方法来完成这些目标。这个项目的结果将提供活体证据 以支持一种以前未被识别的中枢神经系统神经元到神经胶质细胞的通讯模式。它还将提供 迫切需要的细胞生物学知识和洞察力，以了解神经元到胶质细胞的外体信号 沟通，特别是关于miR-124-3p在星形胶质细胞中的非细胞自主遗传调控 内部化。由于神经元到(星形)胶质细胞通讯的改变，显然与许多神经学有关 疾病，这种知识和洞察力可以极大地帮助理解这一途径如何参与中枢神经系统 疾病。

项目成果

Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation.

星形胶质细胞外泌体 HepaCAM 信号传导和 ApoE 拮抗作用协调出生后早期皮质锥体神经元轴突生长和树突棘形成。

• DOI: 10.1101/2023.02.14.528554
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Jin,Shijie;Chen,Xuan;Tian,Yang;Jarvis,Rachel;Promes,Vanessa;Yang,Yongjie
• 通讯作者: Yang,Yongjie

Functionally Clustered mRNAs Are Distinctly Enriched at Cortical Astroglial Processes and Are Preferentially Affected by FMRP Deficiency.

功能性聚集的 mRNA 在皮质星形胶质细胞过程中明显富集，并且优先受到 FMRP 缺陷的影响。

• DOI: 10.1523/jneurosci.0274-22.2022
• 发表时间: 2022
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Men,Yuqin;Higashimori,Haruki;Reynolds,Kathryn;Tu,Leona;Jarvis,Rachel;Yang,Yongjie
• 通讯作者: Yang,Yongjie