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A lysosomal regulatory circuit essential for the development and function of microglia
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.
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Abnormal lysosomes in microglia can negatively alter phagocytic and inflammatory responses, functions known to cause neuroinflammation in AD.
“Abnormal lysosomes in microglia can negatively alter phagocytic and inflammatory responses (Iyer et al. 2022; Lancaster et al. 2021; Quick et al. 2023; Ren et al. 2022), functions known to cause neuroinflammation in ad, substantiating the need to investigate microglia‐specific lysosomal pathways as therapeutic targets.”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Iyer et al. 2022
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Sorted by citations
The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia
Mishra, S., Morshed, N., Sidhu, S. B., Kinoshita, C., Stevens, B., Jayadev, S., & Young, J. E. (2025) · Glia · doi:10.1002/glia.70009 · Cited by 31
Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals
Wu, Y., Guo, W., Kuang, H., Wu, X., Trinh, T. H., Wang, Y., Zhao, S., Wen, Z., & Yu, T. (2025) · eLife · doi:10.7554/elife.105788 · Cited by 9
Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals
Wu, Y., Guo, W., Kuang, H., Wu, X., Trinh, T. H., Wang, Y., Zhao, S., Wen, Z., & Yu, T. (2023) · bioRxiv (Preprint) · doi:10.1101/2023.12.14.570333 · Cited by 1
“Owing to the genetic amenability and the feasibility for live-imaging and lineage tracing, zebrafish has been adopted as an ideal model for the study of microglia development and function (Hughes & Appel, 2020, Iyer, Shen et al., 2022, Li et al., 2012, Peri & Nüsslein-Volhard, 2008).”
Metadata
- Authors
- Iyer, H., Shen, K., Meireles, A. M., & Talbot, W. S.
- Affiliations
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Venue
- Science Advances
- Published
- 2022-09-02
- Volume
- 8
- Issue
- 35
- ISSN
- 2375-2548
- PMC
- PMC9432849
- Cited by
- 49
- References
- 19
- Language
- en
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