PUBLICATION

Fbxw7 Limits Myelination by Inhibiting mTOR Signaling

Authors

Kearns, C.A., Ravanelli, A.M., Cooper, K., Appel, B.

ID

ZDB-PUB-151106-4

Date

2015

Source

The Journal of neuroscience : the official journal of the Society for Neuroscience 35: 14861-71 (Journal)

Registered Authors

Appel, Bruce, Kearns, Christina, Ravanelli, Andrew M.

Keywords

Fbxw7, glia, mTOR, myelin, oligodendrocyte, zebrafish

MeSH Terms

Animals
Animals, Genetically Modified
Cell Cycle Proteins/physiology*
F-Box Proteins/physiology*
Female
Myelin Sheath/metabolism*
Myelin Sheath/ultrastructure
Nerve Fibers, Myelinated/metabolism
Nerve Fibers, Myelinated/ultrastructure
Pregnancy
Signal Transduction/physiology*
TOR Serine-Threonine Kinases/antagonists & inhibitors*
TOR Serine-Threonine Kinases/biosynthesis*
Ubiquitin-Protein Ligases/physiology*
Zebrafish
Zebrafish Proteins/physiology*

(all 16)

PubMed

26538655 Full text @ J. Neurosci.

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.

Genes / Markers

Marker	Marker Type	Name
cldnk	GENE	claudin k
dhrs12	GENE	dehydrogenase/reductase (SDR family) member 12
dhrs12la	GENE	dehydrogenase/reductase 12-like a
fbxw7	GENE	F-box and WD repeat domain containing 7
fdps	GENE	farnesyl diphosphate synthase (farnesyl pyrophosphate synthetase, dimethylallyltranstransferase, geranyltranstransferase)
hmgcra	GENE	3-hydroxy-3-methylglutaryl-CoA reductase a
hmgcs1	GENE	3-hydroxy-3-methylglutaryl-CoA synthase 1 (soluble)
mbpa	GENE	myelin basic protein a
mpz	GENE	myelin protein zero
mtor	GENE	mechanistic target of rapamycin kinase

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Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: sirolimus	Day 4	spinal cord has fewer parts of type oligodendrocyte, abnormal	Fig. 3
WT	chemical treatment: sirolimus	Day 4	whole organism fdps expression decreased amount, abnormal	Fig. 3
WT	chemical treatment: sirolimus	Day 4	whole organism hmgcra expression decreased amount, abnormal	Fig. 3
WT	chemical treatment: sirolimus	Day 4	whole organism hmgcs1 expression decreased amount, abnormal	Fig. 3
WT	chemical treatment: sirolimus	Days 7-13	whole organism ab1-rps6 labeling decreased amount, abnormal	Fig. 4
WT	chemical treatment: sirolimus	Days 7-13	whole organism TOR signaling decreased occurrence, abnormal	Fig. 4
fbxw7^vu56/vu56	standard conditions	Day 4	spinal cord central nervous system myelination increased occurrence, abnormal	Fig. 1
fbxw7^vu56/vu56	standard conditions	Day 4	spinal cord has extra parts of type oligodendrocyte, abnormal	Fig. 3
fbxw7^vu56/vu56	standard conditions	Day 4	spinal cord medial region cldnk expression mislocalised, abnormal	Fig. 1
fbxw7^vu56/vu56	standard conditions	Day 4	spinal cord medial region plp1a expression mislocalised, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
vu12Tg	Tg(olig2:EGFP)	Transgenic Insertion
vu56		Point Mutation	fbxw7
xu015Gt	Gt(GBT-P9)	Transgenic Insertion	mtor

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
fbxw7^vu56/vu56
fbxw7^vu56/vu56; mtor^{xu015Gt/xu015Gt}
fbxw7^vu56/vu56; vu12Tg
mtor^{xu015Gt/xu015Gt}
vu12Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Kearns et al., 2015 ZDB-PUB-151106-4 PMID:26538655

Fbxw7 Limits Myelination by Inhibiting mTOR Signaling

Kearns et al., 2015

ZDB-PUB-151106-4
PMID:26538655