Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system

Mette Harboe; Julie Torvund-Jensen; Kasper Kjaer-Sorensen; Lisbeth Schmidt Laursen

doi:10.1002/glia.23293

Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system

Mette Harboe, Julie Torvund-Jensen, Kasper Kjaer-Sorensen, Lisbeth Schmidt Laursen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

43 Citationer (Scopus)

Abstract

During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.

Originalsprog	Engelsk
Tidsskrift	Glia
Vol/bind	66
Nummer	5
Sider (fra-til)	934-950
Antal sider	17
ISSN	0894-1491
DOI	https://doi.org/10.1002/glia.23293
Status	Udgivet - maj 2018

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10.1002/glia.23293

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title = "Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system",

abstract = "During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.",

keywords = "EphA4, RhoA, axo-glia interaction, myelin, oligodendrocyte",

author = "Mette Harboe and Julie Torvund-Jensen and Kasper Kjaer-Sorensen and Laursen, {Lisbeth Schmidt}",

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AU - Harboe, Mette

AU - Torvund-Jensen, Julie

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AU - Laursen, Lisbeth Schmidt

PY - 2018/5

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N2 - During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.

AB - During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.

KW - EphA4

KW - RhoA

KW - axo-glia interaction

KW - myelin

KW - oligodendrocyte

U2 - 10.1002/glia.23293

DO - 10.1002/glia.23293

M3 - Journal article

C2 - 29350423

SN - 0894-1491

VL - 66

SP - 934

EP - 950

JO - Glia

JF - Glia

IS - 5

ER -

Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system

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