Project 3: Microglia heterogeneity and function in interneuron development

项目 3：小胶质细胞异质性和中间神经元发育中的功能

• 批准号: 10221063
• 负责人: Xianhua Piao
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221063
• 关键词: ADGR1 gene; Address; Adhesions; Anterior; Aorta; Apoptotic; Behavior; Birth; Brain; Brain region; Cell Density; Cell Nucleus; Cells; Cessation of life; Cortical Dysplasia; Crystallization; Cues; Data; Development; Dorsal; Drug Design; Drug Targeting; Exhibits; Family member; Functional disorder; G-Protein-Coupled Receptors; Ganglia; Heterogeneity; Human; Interneurons; Light; Link; Medial; Microglia; Mining; Molecular; Morphology; Mus; Neurodevelopmental Disorder; Neuroglia; Neurons; Pathway interactions; Population; Process; Proliferating; Property; Prosencephalon; Radial; Research; Role; Sampling; Schizophrenia; Small Nuclear RNA; Somatosensory Cortex; Spatial Distribution; Structure; TLR10 gene; Testing; Third Pregnancy Trimester; TimeLine; Toll-like receptors; Transcript; Transgenic Mice; Work; Yolk Sac; age related; autism spectrum disorder; brain cell; brain tissue; cell growth regulation; cell type; conditional knockout; lateral ventricle; lateral ventricle body; macrophage; migration; mouse model; nerve stem cell; neural circuit; neuropsychiatric disorder; novel; postnatal; progenitor; single-cell RNA sequencing; success; transcriptome sequencing; transcriptomics

Abstract Neural circuits require precise placement of correct numbers of interneurons (INs). This delicate process is derailed in neurodevelopmental and neuropsychiatric disease. Microglia, the brain resident macrophages, influence many aspects of brain development, including genesis, migration and maturation of cortical interneurons (cINs). In our preliminary study leading up to this proposal, we discovered diverse molecular and cellular properties of human microglia in the developing forebrain and we found that specific molecularly- defined subtypes are differentially distributed across brain regions. Furthermore, our results show that GPR56 expression defines a subset of human microglia and that deletion of murine microglial Gpr56 leads to a significant reduction in the numbers of PV+ interneurons in specific brain region. However, the full scope of microglia transcriptomic and functional heterogeneity, especially in the human brain, remains elusive. The proposed research will establish the postnatal cellular and molecular heterogeneity of microglia in the human caudal and medial ganglionic eminence with a specific focus on GPR56 in microglia. We hypothesize that microglial GPR56 promotes interneuron development. To test this and corollary hypotheses, we will carry out the following three aims: (1) Define microglia morphology, distribution, and their interactions with neural progenitors (NPCs) and young neurons in the human GEs and the Arc (a unique cluster of migratory interneurons found at birth in the vicinity of the human lateral ventricles); (2) Characterize microglial transcriptomic heterogeneity in the developing hMGE, hCGE and the Arc; and (3) Investigate the cell-type- specific function of microglial GPR56 in interneuron development using microglia-specific conditional knockout mouse model. Most meaningfully, we are conducting our studies using both human brain tissues and transgenic mouse models, to take advantage of the many manipulations that can be done in mice, but always grounding our work in the human conditions we seek to understand. The success of the proposed research will open a novel and important line of research into the origin of neurodevelopmental disorders, such as autism and schizophrenia. Given the status of aGPCRs as drug targets, this line of research carries tremendous translational potential. In particular, it is feasible to begin designing drugs that modify the action of GPR56 given the discovery of its crystal structure.

抽象的 神经回路需要精确放置正确数量的中间神经元（INS）。这个微妙的过程是 在神经发育和神经精神疾病中出轨。小胶质细胞，大脑常驻巨噬细胞， 影响大脑发育的许多方面，包括起源，迁移和皮质成熟 中间神经元（CIN）。在我们的初步研究中，我们发现了各种分子和 人类小胶质细胞在发展前脑中的细胞特性，我们发现特定的分子 定义的亚型分布在大脑区域之间。此外，我们的结果表明GPR56 表达定义了人类小胶质细胞的子集，鼠的小胶质细胞GPR56的缺失导致 特定大脑区域中PV+中间神经元的数量显着减少。但是，全部范围 小胶质细胞转录组和功能异质性，尤其是在人脑中，仍然难以捉摸。这 拟议的研究将建立人类小胶质细胞的产后细胞和分子异质性 小胶质细胞中对GPR56的特定关注的尾尾和内侧神经节卓越。我们假设这一点 小胶质细胞GPR56促进中间神经元的发育。为了测试这个和推论假设，我们将执行 以下三个目的：（1）定义小胶质细胞形态，分布及其与神经的相互作用 祖先（NPC）和人类GE和ARC（独特的迁移群） 在人类外侧心室附近出生时发现的中间神经元）； （2）描述小胶质细胞 发育中的HMGE，HCGE和ARC中的转录组异质性； （3）研究细胞类型 小胶质细胞GPR56在中间神经元开发中使用小胶质细胞特异性敲除 鼠标模型。最有意义地，我们正在使用人脑组织和 转基因鼠标模型，以利用在小鼠中可以进行的许多操作，但始终 在我们寻求理解的人类条件下进行工作。拟议研究的成功将 对神经发育障碍的起源（例如自闭症）开辟一条新颖而重要的研究系列 和精神分裂症。鉴于AGPCR作为药物靶标的地位，这一研究范围很大 翻译潜力。特别是，开始设计修改GPR56作用的药物是可行的 鉴于发现其晶体结构。