Intrinsic control of early microglia development and its impact on neural cell development

早期小胶质细胞发育的内在控制及其对神经细胞发育的影响

• 批准号: 10739972
• 负责人: YASUSHI NAKAGAWA
• 金额: $ 42.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739972
• 关键词: Ablation; Address; Adult; Affect; Animal Model; Axon; Brain; Brain Diseases; Cells; Central Nervous System; Chemicals; Data Analyses; Development; Disease; Embryo; Environmental Risk Factor; Erythro; Event; Gene Expression; Genes; Genetic; Heterogeneity; Hippocampus; Homeostasis; Human; Immune; Immune response; Infection; Intellectual functioning disability; Intervention; Knock-out; Knockout Mice; Mental disorders; Microglia; Molecular; Morphology; Mutant Strains Mice; Myeloid Progenitor Cells; Nervous System; Neurodevelopmental Disorder; Neuroimmune; Neurons; Pathogenesis; Play; Population; Population Heterogeneity; Process; Public Health; Publishing; Research; Research Project Grants; Role; Schizophrenia; Series; Synapses; Testing; Time; Townes-Brocks syndrome; Yolk Sac; Zinc Fingers; aging brain; autism spectrum disorder; axon growth; axon guidance; conditional knockout; cytokine; dominant genetic mutation; immune activation; migration; mutant; nervous system disorder; neurodevelopment; neurogenesis; novel; postnatal; response; single-cell RNA sequencing; spatiotemporal; transcription factor; transcriptome

Origins of many neurodevelopmental disorders such as autism and schizophrenia encompass both genetic and environmental factors. Accumulating evidence indicates that immune response is a key underlying component of both genetic and environmental contributions to these disorders, highlighting the importance of neuroimmune interactions in brain development. Microglia are resident immune cells in the central nervous system and are critical for the homeostasis of adult and aging brains as well as for the pruning of synapses in developing postnatal brains. Microglia appear in early embryonic brains at the time when neurogenesis starts, and undergo a series of changes in gene expression and morphology resulting in temporal and spatial heterogeneity throughout development. Recent studies have addressed whether embryonic microglia influence early neurodevelopmental events by either genetically or chemically ablating microglia or causing systemic maternal immune activation. These studies suggest that early embryonic microglia might have roles in neurogenesis and neuronal migration as well as axon growth and guidance. However, these early roles are not as well understood compared with later developmental roles due to various limitations including: 1) cell ablation cannot address the specific contribution of certain microglia types or states in developing brains, precluding the elucidation of molecular mechanisms, and 2) maternal immune activation not only affects microglia but can also directly impact neural cells. In addition, some of the previous studies show conflicting results on the alteration of neurogenesis in response to microglia ablation. To overcome these limitations, we have developed and analyzed mutant mice in which the zinc finger transcription factor SALL1 is knocked out specifically in microglia. We found by immunostaining and morphology analysis that microglia development is intrinsically perturbed in the absence of SALL1 starting in embryonic brains where neurogenesis and early axon development are underway. In the proposed exploratory research project, we plan to perform single-cell RNA sequencing comparing microglia from Sall1 mutant mice and wild-type controls, and identify the altered microglia subpopulations as well as altered gene expression within each microglia subpopulation. We will next analyze various key aspects early neural development in Sall1 mutant mice and determine whether altered development of microglia impacts these events. By combining the results of these two studies, we expect to develop a valid hypothesis that would explain the molecular underpinnings of early neuroimmune interactions involving diverse microglia populations. In the long term, this project will provide an important positive impact on our understanding of how disrupted microglia development contributes to neurodevelopmental disorders and on subsequent development of novel targeted interventions to treat these disorders.

许多神经发育障碍如自闭症和精神分裂症的起源包括遗传和神经发育障碍。 和环境因素。越来越多的证据表明，免疫反应是一个关键的基础， 遗传和环境因素对这些疾病的贡献，强调了 大脑发育中的神经免疫相互作用。小胶质细胞是中枢神经系统中的常驻免疫细胞 系统，是至关重要的稳态成人和老龄化的大脑，以及修剪突触， 出生后的大脑发育。小胶质细胞出现在早期胚胎大脑中，此时神经发生开始， 并经历一系列基因表达和形态的变化，导致时间和空间的变化。 在整个发展过程中的异质性。最近的研究已经解决了胚胎小胶质细胞是否影响 通过基因或化学消融小胶质细胞或引起全身性神经发育事件， 母体免疫激活。这些研究表明，早期胚胎小胶质细胞可能在 神经发生和神经元迁移以及轴突生长和引导。然而，这些早期的角色并不是 与后来的发育作用相比，由于各种限制，包括：1）细胞消融 不能解决某些小胶质细胞类型或状态在大脑发育中的具体贡献，排除了 阐明了分子机制，2）母体免疫激活不仅影响小胶质细胞， 也直接影响神经细胞。此外，以前的一些研究表明， 对小胶质细胞消融反应的神经发生的改变。 为了克服这些局限性，我们已经开发和分析了突变小鼠，其中锌指 转录因子SALL1在小胶质细胞中被特异性敲除。我们通过免疫染色发现， 形态学分析表明，小胶质细胞的发育在SALL1缺乏的情况下从本质上受到干扰， 神经发生和早期轴突发育正在进行的胚胎大脑。在拟议的探索性 在一个研究项目中，我们计划进行单细胞RNA测序，比较Sall1突变小鼠的小胶质细胞 和野生型对照，并鉴定改变的小胶质细胞亚群以及改变的基因表达 在每个小胶质细胞亚群中。接下来，我们将分析早期神经发育的各个关键方面， Sall1突变小鼠，并确定是否改变小胶质细胞的发展影响这些事件。通过 结合这两项研究的结果，我们希望开发一个有效的假设，可以解释 涉及不同小胶质细胞群体的早期神经免疫相互作用的分子基础。从长远 从长远来看，该项目将对我们理解小胶质细胞如何被破坏产生重要的积极影响。 发展有助于神经发育障碍和随后的发展新的靶向 干预措施来治疗这些疾病。