Wu Linxiu, Xue Rongtao, Chen Jiahao, Xu Jin
School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, China.
Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Cell Death Discov. 2022 Aug 17;8(1):366. doi: 10.1038/s41420-022-01155-6.
Microglia are tissue-resident macrophages that carry out immune functions in the brain. The deficiency or dysfunction of microglia has been implicated in many neurodegenerative disorders. DOCK8, a member of the DOCK family, functions as a guanine nucleotide exchange factor and plays key roles in immune regulation and neurological diseases. The functions of DOCK8 in microglia development are not fully understood. Here, we generated zebrafish dock8 mutants by CRISPR/Cas9 genome editing and showed that dock8 mutations attenuate microglia colonization in the zebrafish midbrain at early larvae stages. In vivo time-lapse imaging revealed that the motility of macrophages was reduced in the dock8 mutant. We further found that cdc42/cdc42l, which encode the small GTPase activated by Dock8, also regulate microglia colonization in zebrafish. Collectively, our study suggests that the Dock8-Cdc42 pathway is required for microglia colonization in zebrafish larvae.
小胶质细胞是驻留在组织中的巨噬细胞，在大脑中执行免疫功能。小胶质细胞的缺乏或功能障碍与许多神经退行性疾病有关。DOCK8是DOCK家族的成员之一，作为鸟嘌呤核苷酸交换因子发挥作用，在免疫调节和神经疾病中起关键作用。DOCK8在小胶质细胞发育中的功能尚未完全了解。在这里，我们通过CRISPR/Cas9基因组编辑生成了斑马鱼dock8突变体，并表明dock8突变会减弱早期幼虫阶段斑马鱼中脑的小胶质细胞定植。体内延时成像显示，dock8突变体中巨噬细胞的运动性降低。我们进一步发现，编码由Dock8激活的小GTP酶的cdc42/cdc42l也调节斑马鱼中的小胶质细胞定植。总的来说，我们的研究表明，Dock8-Cdc42途径是斑马鱼幼虫小胶质细胞定植所必需的。
