CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, PR China.
The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, PR China.
Cell Death Differ. 2021 Jan;28(1):170-183. doi: 10.1038/s41418-020-0591-3. Epub 2020 Jul 24.
Microglia are the primary immune cells in the central nervous system, which plays a vital role in neuron development and neurodegenerative diseases. Microglial precursors in peripheral hematopoietic tissues colonize the central nervous system during early embryogenesis. However, how intrinsic and extrinsic signals integrate to regulate microglia's differentiation remains undefined. In this study, we identified the cerebral white matter hyperintensities susceptibility gene, programmed cell death protein 11 (PDCD11), as an essential factor regulating microglia differentiation. In zebrafish, pdcd11 deficiency prevents the differentiation of the precursors to mature brain microglia. Although, the inflammatory featured macrophage brain colonization is augmented. At 22 h post fertilization, the Pdcd11-positive cells on the yolk sac are distinct from macrophages and neutrophils. Mechanistically, PDCD11 exerts its physiological role by differentially regulating the functions of nuclear factor-kappa B family members, P65 and c-Rel, suppressing P65-mediated expression of inflammatory cytokines, such as tnfα, and enhancing the c-Rel-dependent appearance of tgfβ1. The present study provides novel insights in understanding microglia differentiation during zebrafish development.
小胶质细胞是中枢神经系统中的主要免疫细胞，在神经元发育和神经退行性疾病中起着至关重要的作用。外周造血组织中的小胶质前体细胞在胚胎早期定殖到中枢神经系统。然而，内在和外在信号如何整合来调节小胶质细胞的分化仍不清楚。在这项研究中，我们确定了脑白质高信号易感性基因，程序性细胞死亡蛋白 11（PDCD11），作为调节小胶质细胞分化的必需因素。在斑马鱼中，pdcd11 缺陷阻止了前体细胞向成熟脑小胶质细胞的分化。尽管如此，炎症特征的巨噬细胞脑定植增强了。在受精后 22 小时，卵黄囊上的 Pdcd11 阳性细胞与巨噬细胞和中性粒细胞不同。在机制上，PDCD11 通过差异调节核因子-κB 家族成员 P65 和 c-Rel 的功能来发挥其生理作用，抑制 P65 介导的炎性细胞因子如 tnfα 的表达，并增强 c-Rel 依赖性 tgfβ1 的出现。本研究为理解斑马鱼发育过程中小胶质细胞分化提供了新的见解。
