O'Connor Reed M, Stone Elizabeth F, Wayne Charlotte R, Marcinkevicius Emily V, Ulgherait Matt, Delventhal Rebecca, Pantalia Meghan M, Hill Vanessa M, Zhou Clarice G, McAllister Sophie, Chen Anna, Ziegenfuss Jennifer S, Grueber Wesley B, Canman Julie C, Shirasu-Hiza Mimi M
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032.
Department of Biological Sciences, Columbia University, New York, NY 10025.
J Cell Biol. 2017 Mar 6;216(3):595-605. doi: 10.1083/jcb.201607093. Epub 2017 Feb 21.
Fragile X syndrome, the most common known monogenic cause of autism, results from the loss of FMR1, a conserved, ubiquitously expressed RNA-binding protein. Recent evidence suggests that Fragile X syndrome and other types of autism are associated with immune system defects. We found that mutants exhibit increased sensitivity to bacterial infection and decreased phagocytosis of bacteria by systemic immune cells. Using tissue-specific RNAi-mediated knockdown, we showed that Fmr1 plays a cell-autonomous role in the phagocytosis of bacteria. mutants also exhibit delays in two processes that require phagocytosis by glial cells, the immune cells in the brain: neuronal clearance after injury in adults and the development of the mushroom body, a brain structure required for learning and memory. Delayed neuronal clearance is associated with reduced recruitment of activated glia to the site of injury. These results suggest a previously unrecognized role for Fmr1 in regulating the activation of phagocytic immune cells both in the body and the brain.
脆性X综合征是已知最常见的导致自闭症的单基因病因，它是由FMR1基因缺失引起的，FMR1是一种保守的、广泛表达的RNA结合蛋白。最近的证据表明，脆性X综合征和其他类型的自闭症与免疫系统缺陷有关。我们发现，突变体对细菌感染的敏感性增加，全身免疫细胞对细菌的吞噬作用降低。通过组织特异性RNAi介导的基因敲低，我们表明Fmr1在细菌吞噬过程中发挥细胞自主作用。突变体在两个需要神经胶质细胞（大脑中的免疫细胞）进行吞噬作用的过程中也表现出延迟：成体损伤后的神经元清除以及蘑菇体（学习和记忆所需的脑结构）的发育。延迟的神经元清除与激活的神经胶质细胞向损伤部位的募集减少有关。这些结果表明，Fmr1在调节身体和大脑中吞噬性免疫细胞的激活方面具有以前未被认识到的作用。
