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，通过卫星介导凋亡感觉神经元的吞噬清除 神经胶质细胞在小鼠周围神经系统发育。凋亡碎片的清除也是关键， 中枢神经系统（CNS）的发育和维持，特别是出生后 神经发生神经发生依赖于神经干/祖细胞（NSPC）增殖的偶联， 新生神经元凋亡和凋亡碎片的清除。重要的是，吞噬作用的丧失阻碍了 神经发生在来自雄性和雌性野生型（WT）的脑切片中使用免疫荧光标记 和Jedi-1基因敲除小鼠（JKO）在出生后第一周的生活，我们表明，Jedi-1表达在WT 小胶质细胞存在于出生后的神经原性龛，脑室-脑室下区（V-SVZ），但在 击倒对手因此，我们想知道Jedi-1在小胶质细胞中的表达是否有助于这种偶联， 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 采用体外吞噬试验，发现JKO小胶质细胞显示出显著减少， 相对于WT小胶质细胞的吞噬。这一发现被凋亡细胞的积累所概括。 JKO V-SVZ，如通过TUNEL测定所示。为了确定绝地一号的损失和随后的 小胶质细胞吞噬能力影响神经前体细胞增殖，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小鼠在V-SVZ中具有较少的增殖神经祖细胞 相对于WT小鼠。此外，JKO小鼠的MASH 1+新生神经元数量减少， 与WT小鼠相比。总之，这些数据支持了出生后神经发生是 部分由V-SVZ中凋亡细胞的Jedi-1依赖性小胶质细胞吞噬作用维持。