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.

项目概要 Jedi-1是一种吞噬受体，通过卫星介导凋亡感觉神经元的吞噬清除 发育中的小鼠周围神经系统中的神经胶质细胞。细胞凋亡碎片的清除对于细胞凋亡也至关重要 中枢神经系统（CNS）的发育和维护，特别是产后 神经发生。神经发生依赖于神经干/祖细胞（NSPC）增殖的耦合， 新生神经元凋亡和凋亡碎片的清除。至关重要的是，吞噬作用的丧失会阻碍 神经发生。在雄性和雌性野生型 (WT) 的脑切片中使用免疫荧光标记 和 Jedi-1 敲除小鼠（JKO）在出生后第一周，我们发现 Jedi-1 在 WT 中表达 小胶质细胞存在于出生后神经源性生态位，即心室-心室下区（V-SVZ），但在 淘汰赛。因此，我们想知道小胶质细胞中的 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 的缺失是否会阻碍小胶质细胞的吞噬能力，​​我们 采用体外吞噬测定，发现 JKO 小胶质细胞显示出显着减少 相对于 WT 小胶质细胞的吞噬。这一发现通过细胞凋亡细胞的积累得到了重现。 JKO V-SVZ，如 TUNEL 测定所示。确定 Jedi-1 的丢失以及随后的中断是否 小胶质细胞吞噬能力影响神经前体增殖，我们在出生后进行了 EdU 脉冲 体内第7天。我们的研究结果表明，JKO 小鼠 V-SVZ 中的增殖神经祖细胞较少 相对于WT小鼠。此外，JKO 小鼠的 MASH1+ 新生神经元数量减少 与 WT 小鼠相比。总之，这些数据支持以下假设：出生后神经发生是 部分由 Jedi-1 依赖性小胶质细胞对 V-SVZ 中凋亡细胞的吞噬作用维持。