发育期血管壁周细胞necroptosis通过Slit2/Robo信号触发小胶质前体细胞的脑内迁移

小胶质细胞是起源于卵黄囊，在发育特定阶段由血管迁移入脑的组织定居巨噬细胞，在正常脑发育及各种脑疾病中都发挥重要作用。迄今，发育中调控小胶质前体细胞由血管向脑内迁移的机制仍然不太清楚。我们发现在小胶质前体细胞向脑内迁移的关键时间窗, 血管壁周细胞发生程序性细胞坏死necroptosis;敲除necroptosis关键基因RIPK3和MLKL可致小胶质细胞向脑内的迁移减少，但不影响细胞增殖、凋亡及外周血中巨噬细胞的发育; 同时，坏死的周细胞上调细胞迁移排斥因子Slit2，并在体外排斥小胶质细胞的迁移。我们推测：发育期血管壁周细胞necroptosis可能通过Slit2/Robo信号触发小胶质前体细胞的脑内迁移。本项目拟采用基因修饰小鼠条件性干预周细胞necroptosis及Slit2/Robo信号，以期解析发育期小胶质前体细胞脑内迁移的机制，为理解小胶质细胞的发育与活化规律提供新的视角。

Microglia is the tissue resident macrophage in brain which developmentally derives from yoc sac and immigrates into brain at specific developmental stage. Microglia plays important roles in both normal development of brain and various neurological diseases. However, the mechanism that regulates the migration of microglia progenitors from blood vessels into brain parenchyma still remains unclear. We found that in the critical time window when microglia migrate into brain, some pericytes lining the wall of blood vessel undergo necroptosis, a type of programmed necrosis. Mutation of RIPK3 and MLKL, two key genes in necroptosis, both result in decrease of microglia progenitors in brain parenchyma without affecting proliferation and apoptosis in brain, and macrophage development in periphery blood. In the meanwhile, necroptotic pericytes up-regulate Slit2, a cell migration repelling molecule, and repel the migration of microglia in vitro. Therefore, we speculate that necroptotic pericytes triggers the immigration of microglia progenitors from blood vessels into brain via Slit2/Robo signaling. In the present project, we will investigate this hypothesis by conditional depleting or enhancing necroptosis and conditional manipulating Slit2/Robo signaling, hoping to reveal the underlying mechanism of microglia migration during development, and to shed insight for the understanding of microglial development and activation.