Department of Immunology, Genentech, South San Francisco, California, USA.
Department of Pathology, Genentech, South San Francisco, California, USA.
Nat Immunol. 2017 Jun;18(6):633-641. doi: 10.1038/ni.3743. Epub 2017 May 1.
Microglia and other tissue-resident macrophages within the central nervous system (CNS) have essential roles in neural development, inflammation and homeostasis. However, the molecular pathways underlying their development and function remain poorly understood. Here we report that mice deficient in NRROS, a myeloid-expressed transmembrane protein in the endoplasmic reticulum, develop spontaneous neurological disorders. NRROS-deficient (Nrros) mice show defects in motor functions and die before 6 months of age. Nrros mice display astrogliosis and lack normal CD11bCD45 microglia, but they show no detectable demyelination or neuronal loss. Instead, perivascular macrophage-like myeloid cells populate the Nrros CNS. Cx3cr1-driven deletion of Nrros shows its crucial role in microglial establishment during early embryonic stages. NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function. Our study reveals a NRROS-mediated pathway that controls CNS-resident macrophage development and affects neurological function.
小胶质细胞和中枢神经系统（CNS）中的其他组织驻留巨噬细胞在神经发育、炎症和稳态中发挥着重要作用。然而，其发育和功能的分子途径仍知之甚少。在这里，我们报告说，缺乏内质网中髓系表达的跨膜蛋白 NRROS 的小鼠会自发出现神经疾病。NRROS 缺陷（Nrros）小鼠表现出运动功能缺陷，并在 6 个月大之前死亡。Nrros 小鼠表现出星形胶质细胞增生，缺乏正常的 CD11bCD45 小胶质细胞，但没有检测到明显的脱髓鞘或神经元丢失。相反，血管周巨噬细胞样髓样细胞在 Nrros 的中枢神经系统中定植。Cx3cr1 驱动的 Nrros 缺失显示其在早期胚胎阶段对小胶质细胞建立的关键作用。NRROS 是正常表达 Sall1 和其他小胶质细胞基因所必需的，这些基因对小胶质细胞的发育和功能很重要。我们的研究揭示了一个由 NRROS 介导的途径，该途径控制中枢神经系统驻留巨噬细胞的发育并影响神经功能。
