EphB3 receptors function as dependence receptors to mediate oligodendrocyte cell death following contusive spinal cord injury

Tsenkina, Yanina; Ricard, Jacques; Runko, Erik; Acosta, Maria; Mier, José M.; Liebl, Daniel J.

doi:10.1038/cddis.2015.262

Cited by 17 publications

(19 citation statements)

References 61 publications

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“…The Eph-family consists of 14 receptors, divided into two subclasses, EphA and EphB, based on their preference for ligand binding. Ephs and ephrins of both subclasses are expressed on oligodendrocytes (Linneberg, Harboe, & Laursen, 2015;Prestoz et al, 2004;Tsenkina et al, 2015), and in vitro data indicate that signaling through EphA or EphB in the oligodendrocyte prevents process extension, whereas signaling though ephrin-B enhances myelin sheet formation (Linneberg et al, 2015). However, there are exceptions to this, as EphA4 has also been reported to interact with ephrin-B (Kullander & Klein, 2002), albeit with a 10-fold lower affinity (Qin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…However, there are exceptions to this, as EphA4 has also been reported to interact with ephrin-B (Kullander & Klein, 2002), albeit with a 10-fold lower affinity (Qin et al, 2010). Ephs and ephrins of both subclasses are expressed on oligodendrocytes (Linneberg, Harboe, & Laursen, 2015;Prestoz et al, 2004;Tsenkina et al, 2015), and in vitro data indicate that signaling through EphA or EphB in the oligodendrocyte prevents process extension, whereas signaling though ephrin-B enhances myelin sheet formation (Linneberg et al, 2015). How the individual members of the Eph-ephrin families might be involved in the myelination process is, however, unknown.…”

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confidence: 99%

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

Harboe

Torvund-Jensen

Kjær-Sørensen

et al. 2018

Glia

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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.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Harboe

Torvund-Jensen

Kjær-Sørensen

et al. 2018

Glia

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“…It was revealed that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and acts as myelin-based inhibitor through a combined p75 neurotrophin receptor ( 136 ). A previous study demonstrated that EphB3 functions as a dependence receptor that mediates oligodendrocyte cell death following SCI, which further supports the development of ephrin-B3 based therapies to promote recovery ( 137 ).…”

Section: Expression and Regulation Of Eph Receptors And Ephrins In Thmentioning

confidence: 57%

Roles of Eph/ephrin bidirectional signaling in central nervous system injury and recovery (Review)

et al. 2018

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Multiple cellular components are involved in the complex pathological process following central nervous system (CNS) injury, including neurons, glial cells and endothelial cells. Previous studies and neurotherapeutic clinical trials have assessed the molecular mechanisms that underlie neuronal cell death following CNS injury. However, this approach has largely failed to reduce CNS damage or improve the functional recovery of patients. Erythropoietin-producing human hepatocellular (Eph) receptors and ephrin ligands have attracted considerable attention since their discovery, due to their extensive distribution and unique bidirectional signaling between astrocytes and neurons. Previous studies have investigated the roles of Eph/ephrin bidirectional signaling in the developing central nervous system. It was determined that Eph/ephrin bidirectional signaling is expressed in various CNS regions and cell types, and that it serves diverse roles in the adult CNS. In the present review, the roles of Eph/ephrin bidirectional signaling in CNS injuries are assessed.

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“…In recent years, Eph receptors have been found to have pro-apoptotic responses following traumatic central nervous system (CNS) injury 19 – 21 , and are now classified as new members of a larger “dependence receptor” family 22 . Dependence receptors are transmembrane proteins that have dual opposing roles depending on the availability of their corresponding ligand.…”

Section: Introductionmentioning

confidence: 99%

“…When the ligand is present, these receptors can promote normal development and tissue homeostasis by inducing ligand-mediated positive signals 24 , 25 . Currently, two Eph receptors, EphA4 and EphB3, have been found to have dependence receptor functions in the naive and injured adult CNS 20 , 21 , 23 , 26 . Here, we describe a new dependence receptor role for EphB3 in regulating cerebral vascular EC survival after TBI.…”

Section: Introductionmentioning

confidence: 99%

EphB3 signaling induces cortical endothelial cell death and disrupts the blood–brain barrier after traumatic brain injury

2018

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Damage to the cerebrovascular network is a major contributor to dysfunction in patients suffering from traumatic brain injury (TBI). Vessels are composed of lumen-forming endothelial cells that associate closely with both glial and neuronal units to establish a functional blood–brain barrier (BBB). Under normal physiological conditions, these vascular units play important roles in central nervous system (CNS) homeostasis by delivering oxygen and nutrients while filtering out molecules and cells that could be harmful; however, after TBI this system is disrupted. Here, we describe a novel role for a class of receptors, called dependence receptors, in regulating vessel stability and BBB integrity after CCI injury in mice. Specifically, we identified that EphB3 receptors function as a pro-apoptotic dependence receptor in endothelial cells (ECs) that contributes to increased BBB damage after CCI injury. In the absence of EphB3, we observed increased endothelial cell survival, reduced BBB permeability and enhanced interactions of astrocyte-EC membranes. Interestingly, the brain’s response to CCI injury is to reduce EphB3 levels and its ligand ephrinB3; however, the degree and timing of those reductions limit the protective response of the CNS. We conclude that EphB3 is a negative regulator of cell survival and BBB integrity that undermine tissue repair, and represents a protective therapeutic target for TBI patients.

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EphB3 receptors function as dependence receptors to mediate oligodendrocyte cell death following contusive spinal cord injury

Cited by 17 publications

References 61 publications

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

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

Roles of Eph/ephrin bidirectional signaling in central nervous system injury and recovery (Review)

EphB3 signaling induces cortical endothelial cell death and disrupts the blood–brain barrier after traumatic brain injury

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