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A lysosomal regulatory circuit essential for the development and function of microglia

Authors: 
Iyer H, Shen K, Meireles AM, Talbot WS
Citation: 
Sci Adv. 2022 Sep 2;8(35):eabp8321. doi: 10.1126/sciadv.abp8321. Epub 2022 Aug 31
Abstract: 
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 rraga 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.
Epub: 
Not Epub
Organism or Cell Type: 
zebrafish
Delivery Method: 
microinjection