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

Ana M. Meireles; Kimberle  Shen; Lida Zoupi; Harini  Iyer; Ellen L.  Bouchard; Anna Williams; William S Talbot

doi:10.1016/j.devcel.2018.10.003

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

Ana M. Meireles, Kimberle Shen, Lida Zoupi, Harini Iyer, Ellen L. Bouchard, Anna Williams, William S Talbot

Centre for Regenerative Medicine

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Journal	Developmental Cell
DOIs	https://doi.org/10.1016/j.devcel.2018.10.003
Publication status	Published - 5 Nov 2018

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10.1016/j.devcel.2018.10.003

DEVELOPMENTAL-CELL-D-18-00231_R4Accepted author manuscript, 8.96 MB

Anna Williams
- Deanery of Clinical Sciences - Personal chair of Regenerative neurology
- Centre for Regenerative Medicine
- Anne Rowling Regenerative Neurology Clinic
- Edinburgh Neuroscience
Person: Academic: Research Active

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title = "The Lysosomal Transcription Factor TFEB represses myelination downstream of the Rag-Ragulator complex",

abstract = "Myelin allows for fast and efficient axonal conduction, but much remains to be determined aboutthe 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 GproteinRagA is essential for CNS myelination. In rraga-/- mutant oligodendrocytes, target genes of thelysosomal transcription factor Tfeb are upregulated, consistent with previous evidence thatRagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagAmutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb-/- singlemutants exhibit ectopic myelin, further indicating that Tfeb represses myelination duringdevelopment. In a mouse model of de- and remyelination, TFEB expression is increased inoligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especiallyduring remyelination. These results define essential regulators of myelination and may advanceapproaches to therapeutic remyelination.",

author = "Meireles, {Ana M.} and Kimberle Shen and Lida Zoupi and Harini Iyer and Bouchard, {Ellen L.} and Anna Williams and Talbot, {William S}",

year = "2018",

month = nov,

day = "5",

doi = "10.1016/j.devcel.2018.10.003",

language = "English",

journal = "Developmental Cell",

issn = "1534-5807",

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TY - JOUR

T1 - The Lysosomal Transcription Factor TFEB represses myelination downstream of the Rag-Ragulator complex

AU - Meireles, Ana M.

AU - Shen, Kimberle

AU - Zoupi, Lida

AU - Iyer, Harini

AU - Bouchard, Ellen L.

AU - Williams, Anna

AU - Talbot, William S

PY - 2018/11/5

Y1 - 2018/11/5

N2 - Myelin allows for fast and efficient axonal conduction, but much remains to be determined aboutthe 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 GproteinRagA is essential for CNS myelination. In rraga-/- mutant oligodendrocytes, target genes of thelysosomal transcription factor Tfeb are upregulated, consistent with previous evidence thatRagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagAmutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb-/- singlemutants exhibit ectopic myelin, further indicating that Tfeb represses myelination duringdevelopment. In a mouse model of de- and remyelination, TFEB expression is increased inoligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especiallyduring remyelination. These results define essential regulators of myelination and may advanceapproaches to therapeutic remyelination.

AB - Myelin allows for fast and efficient axonal conduction, but much remains to be determined aboutthe 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 GproteinRagA is essential for CNS myelination. In rraga-/- mutant oligodendrocytes, target genes of thelysosomal transcription factor Tfeb are upregulated, consistent with previous evidence thatRagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore myelination in RagAmutants, indicating that hyperactive Tfeb represses myelination. Conversely, tfeb-/- singlemutants exhibit ectopic myelin, further indicating that Tfeb represses myelination duringdevelopment. In a mouse model of de- and remyelination, TFEB expression is increased inoligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especiallyduring remyelination. These results define essential regulators of myelination and may advanceapproaches to therapeutic remyelination.

U2 - 10.1016/j.devcel.2018.10.003

DO - 10.1016/j.devcel.2018.10.003

M3 - Article

SN - 1534-5807

JO - Developmental Cell

JF - Developmental Cell

ER -

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

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