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The Lysosomal Transcription Factor TFEB represses myelination downstream of the Rag-Ragulator complex

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Original languageEnglish
JournalDevelopmental Cell
DOIs
Publication statusPublished - 5 Nov 2018

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 Gprotein
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.

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