Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 44, Pages 14861-14871Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4968-14.2015
Keywords
Fbxw7; glia; mTOR; myelin; oligodendrocyte; zebrafish
Categories
Funding
- National Institutes of Health (NIH) [RO1 NS046668]
- Gates Frontiers Fund
- NIH [P30 NS048154]
- National Institutes of Health (National Cancer Institute) [5T32CA08208613]
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An important characteristic of vertebrate CNS development is the formation of specific amounts of insulating myelin membrane on axons. CNS myelin is produced by oligodendrocytes, glial cells that extend multiple membrane processes to wrap multiple axons. Recent data have shown that signaling mediated by the mechanistic target of rapamycin (mTOR) serine/threonine kinase promotes myelination, but factors that regulate mTOR activity for myelination remain poorly defined. Through a forward genetic screen in zebrafish, we discovered that mutation of fbxw7, which encodes the substrate recognition subunit of a SCF ubiquitin ligase that targets proteins for degradation, causes hypermyelination. Among known Fbxw7 targets is mTOR. Here, we provide evidence that mTOR signaling activity is elevated in oligodendrocyte lineage cells of fbxw7 mutant zebrafish larvae. Both genetic and pharmacological inhibition of mTOR function suppressed the excess myelin gene expression resulting from loss of Fbxw7 function, indicating that mTOR is a functionally relevant target of Fbxw7 in oligodendrocytes. fbxw7 mutant larvae wrapped axons with more myelin membrane than wild-type larvae and oligodendrocyte-specific expression of dominant-negative Fbxw7 produced longer myelin sheaths. Our data indicate that Fbxw7 limits the myelin-promoting activity of mTOR, thereby serving as an important brake on developmental myelination.
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