PUBLICATION
The Akt-mTOR pathway drives myelin sheath growth by regulating cap-dependent translation
- Authors
- Fedder-Semmes, K.N., Appel, B.
- ID
- ZDB-PUB-210904-1
- Date
- 2021
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 41(41): 8532-8544 (Journal)
- Registered Authors
- Appel, Bruce
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Female
- Humans
- Male
- Myelin Sheath/genetics
- Myelin Sheath/metabolism*
- Protein Biosynthesis/physiology*
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism*
- RNA Caps/genetics
- RNA Caps/metabolism*
- Signal Transduction/physiology*
- TOR Serine-Threonine Kinases/genetics
- TOR Serine-Threonine Kinases/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 34475201 Full text @ J. Neurosci.
Citation
Fedder-Semmes, K.N., Appel, B. (2021) The Akt-mTOR pathway drives myelin sheath growth by regulating cap-dependent translation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 41(41):8532-8544.
Abstract
In the vertebrate central nervous system, oligodendrocytes produce myelin, a specialized membrane, to insulate and support axons. Individual oligodendrocytes wrap multiple axons with myelin sheaths of variable lengths and thicknesses. Myelin grows at the distal ends of oligodendrocyte processes and multiple lines of work have provided evidence that mRNAs and RNA binding proteins localize to myelin, together supporting a model where local translation controls myelin sheath growth. What signal transduction mechanisms could control this? One strong candidate is the Akt-mTOR pathway, a major cellular signaling hub that coordinates transcription, translation, metabolism, and cytoskeletal organization. Here, using zebrafish as a model system, we found that Akt-mTOR signaling promotes myelin sheath growth and stability during development. Through cell-specific manipulations to oligodendrocytes, we show that the Akt-mTOR pathway drives cap-dependent translation to promote myelination and that restoration of cap-dependent translation is sufficient to rescue myelin deficits in mTOR loss-of-function animals. Moreover, an mTOR-dependent translational regulator was phosphorylated and co-localized with mRNA encoding a canonically myelin-translated protein in vivo and bioinformatic investigation revealed numerous putative translational targets in the myelin transcriptome. Together, these data raise the possibility that Akt-mTOR signaling in nascent myelin sheaths promotes sheath growth via translation of myelin-resident mRNAs during development.SIGNIFICANCE STATEMENTIn the brain and spinal cord oligodendrocytes extend processes that tightly wrap axons with myelin, a protein and lipid rich membrane that increases electrical impulses and provides trophic support. Myelin membrane grows dramatically following initial axon wrapping in a process that demands protein and lipid synthesis. How protein and lipid synthesis is coordinated with the need for myelin to be generated in certain locations remains unknown. Our study reveals that the Akt-mTOR signaling pathway promotes myelin sheath growth by regulating protein translation. Because we found translational regulators of the Akt-mTOR pathway in myelin, our data raise the possibility Akt-mTOR activity regulates translation in myelin sheaths to deliver myelin on demand to the places it is needed.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping