Loss of Jedi-1 impairs microglia phagocytosis, resulting in reduced postnatal neurogenesis in the ventricular-subventricular zone.

Jedi-1 的缺失会损害小胶质细胞的吞噬作用，导致脑室-脑室下区的出生后神经发生减少。

• 批准号: 10704464
• 负责人: Vivianne E Morrison
• 金额: $ 7.68万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704464
• 关键词: 3-Dimensional; ASCL1 gene; Address; Adult; Afferent Neurons; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Basic Science; Behavior; Biological Assay; Biology; Brain; Brain Diseases; Cell Communication; Cell Shape; Cells; Central Nervous System; Clinical; Coupling; Data; Defect; Development; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Female; Funding; Impairment; In Vitro; Inflammatory; Interneurons; Knock-out; Knockout Mice; Knowledge; Label; Life; Longevity; Maintenance; Mediating; Microglia; Morphology; Mus; Nature; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; Pathway interactions; Patients; Peripheral Nervous System; Phagocytes; Phagocytosis; Phenotype; Physiologic pulse; Play; Population; Primates; Process; Production; Proliferating; Quality of life; Rodent; Role; Signal Transduction; Stains; Surface; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Translating; Ventricular; Wild Type Mouse; cell motility; cytokine; experimental study; extracellular; improved; in vivo; knowledge base; live cell imaging; male; nerve stem cell; neuroblast; neurogenesis; neuron apoptosis; neuron loss; newborn neuron; novel; olfactory bulb; postnatal; prevent; receptor; receptor expression; receptor function; reconstruction; regenerative; relating to nervous system; stem; stem cell proliferation; stem cell survival; stem cells; subventricular zone; targeted treatment

Project Summary Jedi-1 is an engulfment receptor that mediates phagocytic clearance of apoptotic sensory neurons by satellite glia in the developing murine peripheral nervous system. The clearance of apoptotic debris is also critical for the development and maintenance of the central nervous system (CNS), in particular for postnatal neurogenesis. Neurogenesis relies on the coupling of neural stem/progenitor cell (NSPC) proliferation, newborn neuron apoptosis, and clearance of the apoptotic debris. Critically, loss of phagocytosis hinders neurogenesis. Using immunofluorescent labeling in brain sections from male and female wildtype (WT) and Jedi-1 knockout mice (JKO) in the first week of postnatal life, we show that Jedi-1 is expressed in WT microglia residing in the postnatal neurogenic niche, the ventricular-subventricular zone (V-SVZ), but absent in the knockout. Therefore, we asked whether Jedi-1 expression in microglia contributes to this coupling and thereby regulates neurogenesis. To test whether loss of Jedi-1 hinders microglial phagocytic ability, we employed an in vitro engulfment assay and found that JKO microglia display a significant reduction in engulfment relative to WT microglia. This finding was recapitulated by an accumulation of apoptotic cells in the JKO V-SVZ, as shown by TUNEL assay. To determine whether loss of Jedi-1 and subsequent disruption of microglial phagocytic ability impacts neural precursor proliferation, we performed an EdU pulse at postnatal day 7 in vivo. Our findings demonstrate that JKO mice have fewer proliferating neural progenitors in the V-SVZ relative to WT mice. Furthermore, JKO mice have reduced numbers of MASH1+ newborn neurons when compared to those of WT mice. Together, these data support the hypothesis that postnatal neurogenesis is maintained in part by Jedi-1-dependent microglial phagocytosis of apoptotic cells in the V-SVZ.

项目摘要 JEDI-1是一种吞噬受体，可通过卫星介导凋亡感觉神经元的吞噬性清除率 发育中的鼠周围神经系统中的神经胶质。凋亡碎片的清除对于 中枢神经系统（CNS）的开发和维护，特别是在产后 神经发生。神经发生取决于神经茎/祖细胞（NSPC）增殖的偶联， 新生儿神经元细胞凋亡和凋亡碎片的清除。至关重要的是吞噬作用的丧失 神经发生。在男性和女性野生型（WT）中使用脑部的免疫荧光标记（WT） 和Jedi-1淘汰小鼠（JKO）在产后生活的第一周，我们证明JEDI-1在WT中表达 居住在产后神经源性小裂中的小胶质细胞，心室 - 腔室区（V-SVZ），但不存在于 淘汰赛。因此，我们询问小胶质细胞中的JEDI-1表达是否有助于这种耦合和 从而调节神经发生。为了测试JEDI-1的损失是否阻碍小胶质细胞吞噬能力，​​我们 采用了一种体外吞噬分析，发现JKO小胶质细胞显示出显着降低 相对于WT小胶质细胞吞噬。通过凋亡细胞在 JKO V-SVZ，如Tunel分析所示。确定JEDI-1的丢失以及随后的破坏 小胶质细胞吞噬能力影响神经前体的增殖，我们在产后进行了EDU脉冲 第七天在体内。我们的发现表明，JKO小鼠在V-SVZ中的神经祖细胞的增殖较少 相对于WT小鼠。此外，当JKO小鼠减少了Mash1+新生神经元的数量 与WT小鼠相比。总之，这些数据支持了下产后神经发生是 V-SVZ中凋亡细胞的JEDI-1依赖性小胶质细胞吞噬作用部分维持。