PUBLICATION
The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex
- Authors
- Meireles, A.M., Shen, K., Zoupi, L., Iyer, H., Bouchard, E.L., Williams, A., Talbot, W.S.
- ID
- ZDB-PUB-181107-12
- Date
- 2018
- Source
- Developmental Cell 47: 319-330.e5 (Journal)
- Registered Authors
- Talbot, William S.
- Keywords
- RagA, TFEB, glia, lysosomes, myelin, myelination, oligodendrocytes, zebrafish
- Datasets
- GEO:GSE119332
- MeSH Terms
-
- Male
- Mice
- Nerve Fibers, Myelinated/metabolism
- Mice, Inbred C57BL
- Lysosomes/metabolism
- Lysosomes/physiology
- Monomeric GTP-Binding Proteins/metabolism
- Animals
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Zebrafish Proteins/physiology
- Signal Transduction
- Oligodendroglia/physiology
- Endosomes/metabolism
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism*
- Myelin Sheath/metabolism*
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism*
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/physiology
- TOR Serine-Threonine Kinases/metabolism
- Zebrafish
- Intracellular Membranes/metabolism
- PubMed
- 30399334 Full text @ Dev. Cell
Citation
Meireles, A.M., Shen, K., Zoupi, L., Iyer, H., Bouchard, E.L., Williams, A., Talbot, W.S. (2018) The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex. Developmental Cell. 47:319-330.e5.
Abstract
Myelin allows for fast and efficient axonal conduction, but much remains to be determined about the mechanisms that regulate myelin formation. To investigate the genetic basis of myelination, we carried out a genetic screen using zebrafish. Here, we show that the lysosomal G protein RagA is essential for CNS myelination. In rraga-/- mutant oligodendrocytes, target genes of the lysosomal transcription factor Tfeb are upregulated, consistent with previous evidence that RagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagA mutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb-/- single mutants exhibit ectopic myelin, further indicating that Tfeb represses myelination during development. In a mouse model of de- and remyelination, TFEB expression is increased in oligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especially during remyelination. These results define essential regulators of myelination and may advance approaches to therapeutic remyelination.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping