Iyer Harini, Shen Kimberle, Meireles Ana M, Talbot William S
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Adv. 2022 Sep 2;8(35):eabp8321. doi: 10.1126/sciadv.abp8321. Epub 2022 Aug 31.
As the primary phagocytic cells of the central nervous system, microglia exquisitely regulate their lysosomal activity to facilitate brain development and homeostasis. However, mechanisms that coordinate lysosomal activity with microglia development, chemotaxis, and function remain unclear. Here, we show that embryonic macrophages require the lysosomal guanosine triphosphatase (GTPase) RagA and the GTPase-activating protein Folliculin to colonize the brain in zebrafish. We demonstrate that embryonic macrophages in mutants show increased expression of lysosomal genes but display significant down-regulation of immune- and chemotaxis-related genes. Furthermore, we find that RagA and Folliculin repress the key lysosomal transcription factor Tfeb and its homologs Tfe3a and Tfe3b in the macrophage lineage. Using RNA sequencing, we establish that Tfeb and Tfe3 are required for activation of lysosomal target genes under conditions of stress but not for basal expression of lysosomal pathways. Collectively, our data define a lysosomal regulatory circuit essential for macrophage development and function in vivo.
作为中枢神经系统的主要吞噬细胞，小胶质细胞精确调节其溶酶体活性以促进大脑发育和稳态。然而，协调溶酶体活性与小胶质细胞发育、趋化性和功能的机制仍不清楚。在这里，我们表明胚胎巨噬细胞需要溶酶体鸟苷三磷酸酶（GTP酶）RagA和GTP酶激活蛋白卵泡抑素才能在斑马鱼中定殖于大脑。我们证明，突变体中的胚胎巨噬细胞显示溶酶体基因表达增加，但免疫和趋化相关基因显著下调。此外，我们发现RagA和卵泡抑素在巨噬细胞谱系中抑制关键的溶酶体转录因子Tfeb及其同源物Tfe3a和Tfe3b。通过RNA测序，我们确定Tfeb和Tfe3在应激条件下是激活溶酶体靶基因所必需的，但不是溶酶体途径基础表达所必需的。总的来说，我们的数据定义了一个体内巨噬细胞发育和功能所必需的溶酶体调节回路。
