Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, 34988, Israel.
Department of Genetics and Developmental Biology, The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, 31096, Israel.
Glia. 2018 Jul;66(7):1520-1532. doi: 10.1002/glia.23322. Epub 2018 Mar 9.
Development of the central nervous system involves elimination of superfluous neurons through apoptosis and subsequent phagocytosis. In Drosophila, this occurs mainly during three developmental stages: embryogenesis, metamorphosis and emerging adult. Two transmembrane glial phagocytic receptors, SIMU (homolog of the mammalian Stabilin-2) and Draper (homolog of the mammalian MEGF10 and Jedi), mediate glial phagocytosis of apoptotic neurons during embryogenesis. However, less is known about the removal of apoptotic neurons during later stages of development. Here we show that during metamorphosis, Draper plays a critical role in apoptotic cell clearance by glia, whereas SIMU, which is mostly expressed in pupal macrophages outside the brain, is not involved in glial phagocytosis. We found that Draper activates Drosophila c-Jun N-terminal kinase (dJNK) signaling predominantly in the ensheathing glia and astrocytes, where it is required for efficient removal of apoptotic neurons. Our data suggest that besides the dJNK pathway, Draper also triggers an additional signaling pathway capable of removing apoptotic neurons in the pupal brain. This study thus reveals that SIMU unexpectedly is not involved in glial phagocytosis of apoptotic neurons during metamorphosis and highlights the novel role of dJNK signaling in developmental apoptotic cell clearance downstream of Draper.
中枢神经系统的发育涉及通过细胞凋亡和随后的吞噬作用消除多余的神经元。在果蝇中，这主要发生在三个发育阶段：胚胎发生、变态和新兴成虫。两种跨膜神经胶质吞噬受体，SIMU（哺乳动物 Stabilin-2 的同源物）和 Draper（哺乳动物 MEGF10 和 Jedi 的同源物），介导胚胎发生过程中神经胶质吞噬凋亡神经元。然而，对于发育后期凋亡神经元的清除，人们知之甚少。在这里，我们表明在变态期间，Draper 通过神经胶质在凋亡细胞清除中起着关键作用，而主要在大脑外的蛹巨噬细胞中表达的 SIMU 则不参与神经胶质吞噬。我们发现 Draper 主要在包绕神经胶质和星形胶质细胞中激活果蝇 c-Jun N 端激酶（dJNK）信号通路，这对于有效清除凋亡神经元是必需的。我们的数据表明，除了 dJNK 途径外，Draper 还触发了另一种能够在蛹脑中清除凋亡神经元的信号通路。因此，这项研究表明，出乎意料的是，SIMU 不参与变态过程中神经胶质吞噬凋亡神经元，并且突出了 dJNK 信号在 Draper 下游发育性凋亡细胞清除中的新作用。
