PUBLICATION
A lysosomal regulatory circuit essential for the development and function of microglia
- Authors
- Iyer, H., Shen, K., Meireles, A.M., Talbot, W.S.
- ID
- ZDB-PUB-220901-6
- Date
- 2022
- Source
- Science advances 8: eabp8321 (Journal)
- Registered Authors
- Talbot, William S.
- Keywords
- none
- Datasets
- GEO:GSE197349, GEO:GSE197348, GEO:GSE197350
- MeSH Terms
- none
- PubMed
- 36044568 Full text @ Sci Adv
Citation
Iyer, H., Shen, K., Meireles, A.M., Talbot, W.S. (2022) A lysosomal regulatory circuit essential for the development and function of microglia. Science advances. 8:eabp8321.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping