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Fbxw7 Limits Myelination by Inhibiting mTOR Signaling.
J Neurosci 2015; 35(44):14861-71JN

Abstract

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.

SIGNIFICANCE STATEMENT

Myelin, a specialized, proteolipid-rich membrane that ensheaths and insulates nerve fibers, facilitates the rapid conduction of electrical impulses over long distances. Abnormalities in myelin formation or maintenance result in intellectual and motor disabilities, raising a need for therapeutic strategies designed to promote myelination. The mTOR kinase is a powerful driver of myelination, but the mechanisms that regulate mTOR function in myelination are not well understood. Our studies reveal that Fbxw7, a subunit of a ubiquitin ligase that targets other proteins for degradation, acts as a brake on myelination by limiting mTOR function. These findings suggest that Fbxw7 helps tune the amount of myelin produced during development and raise the possibility that Fbxw7 could be a target of myelin-promoting therapies.

Authors+Show Affiliations

Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045.Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045.Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045.Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045 bruce.appel@ucdenver.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26538655

Citation

Kearns, Christina A., et al. "Fbxw7 Limits Myelination By Inhibiting mTOR Signaling." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 35, no. 44, 2015, pp. 14861-71.
Kearns CA, Ravanelli AM, Cooper K, et al. Fbxw7 Limits Myelination by Inhibiting mTOR Signaling. J Neurosci. 2015;35(44):14861-71.
Kearns, C. A., Ravanelli, A. M., Cooper, K., & Appel, B. (2015). Fbxw7 Limits Myelination by Inhibiting mTOR Signaling. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 35(44), pp. 14861-71. doi:10.1523/JNEUROSCI.4968-14.2015.
Kearns CA, et al. Fbxw7 Limits Myelination By Inhibiting mTOR Signaling. J Neurosci. 2015 Nov 4;35(44):14861-71. PubMed PMID: 26538655.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fbxw7 Limits Myelination by Inhibiting mTOR Signaling. AU - Kearns,Christina A, AU - Ravanelli,Andrew M, AU - Cooper,Kirsten, AU - Appel,Bruce, PY - 2015/11/6/entrez PY - 2015/11/6/pubmed PY - 2016/2/13/medline KW - Fbxw7 KW - glia KW - mTOR KW - myelin KW - oligodendrocyte KW - zebrafish SP - 14861 EP - 71 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 35 IS - 44 N2 - UNLABELLED: 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. SIGNIFICANCE STATEMENT: Myelin, a specialized, proteolipid-rich membrane that ensheaths and insulates nerve fibers, facilitates the rapid conduction of electrical impulses over long distances. Abnormalities in myelin formation or maintenance result in intellectual and motor disabilities, raising a need for therapeutic strategies designed to promote myelination. The mTOR kinase is a powerful driver of myelination, but the mechanisms that regulate mTOR function in myelination are not well understood. Our studies reveal that Fbxw7, a subunit of a ubiquitin ligase that targets other proteins for degradation, acts as a brake on myelination by limiting mTOR function. These findings suggest that Fbxw7 helps tune the amount of myelin produced during development and raise the possibility that Fbxw7 could be a target of myelin-promoting therapies. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/26538655/Fbxw7_Limits_Myelination_by_Inhibiting_mTOR_Signaling_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=26538655 DB - PRIME DP - Unbound Medicine ER -