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.

The oligodendrocyte growth cone and its actin cytoskeleton: A fundamental element for progenitor cell migration and CNS myelination

“…Members of the IgLON family, which represent GPI anchored adhesion molecules expressed by both OLGs and neurons, have also been identified as repulsive cues with functional importance in preventing precocious developmental myelination of specific fiber tracts (Sharma et al, ). Specific axon selection for myelination has additionally been reported to involve bidirectional Eph‐ephrin signaling, whereby OLG process retraction in response to ephrin A1‐EphA4 forward signaling was found to be mediated by a signaling cascade involving RhoA, the RhoA downstream target Rho kinase (ROCK) and the motor protein myosin II (Cohen, ; Harboe, Torvund‐Jensen, Kjaer‐Sorensen, & Laursen, ; Linneberg, Harboe, & Laursen, ). This finding provides evidence for a critical role of RhoA in driving the actin cytoskeletal changes that ultimately lead to process retraction when differentiating OLGs respond to nonpermissive cues.…”

The Rules of Attraction in Central Nervous System Myelination

“…Negative regulators include some of the Eph-ephrin molecules expressed in axons and oligodendrocyte-lineage cells. Axonal ephrin-A1/B2 forward signaling through EphA/B receptors on oligodendrocytes can induce process retraction and reduce myelination in vitro and in vivo ( Linneberg et al, 2015 ; Harboe et al, 2018 ). Indeed, ephrin-A1 expression in neurons reduced their myelination in the zebrafish spinal cord, by interacting with the EphA4 receptor on oligodendrocytes, whose knockdown increased the number of axons myelinated by individual oligodendrocytes ( Harboe et al, 2018 ).…”

“…Axonal ephrin-A1/B2 forward signaling through EphA/B receptors on oligodendrocytes can induce process retraction and reduce myelination in vitro and in vivo ( Linneberg et al, 2015 ; Harboe et al, 2018 ). Indeed, ephrin-A1 expression in neurons reduced their myelination in the zebrafish spinal cord, by interacting with the EphA4 receptor on oligodendrocytes, whose knockdown increased the number of axons myelinated by individual oligodendrocytes ( Harboe et al, 2018 ). Ephrin-Eph binding induces both forward signaling in the receptor-expressing cell and reverse signaling in the ephrin-expressing cell which can be regulated independently ( Pasquale, 2008 ).…”

New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination

“…Therefore, we wanted to test whether enhancing their process extension and ability to make new sheaths improved their remyelination capacity. To do so, we inhibited Rho Kinase (ROCK) following demyelination, using the inhibitor Y27632, which increases the number of myelin sheaths made by oligodendrocytes in zebrafish and mammals (39)(40)(41). We found that inhibition of ROCK did not significantly affect the number or length of myelin sheaths made on axons by oligodendrocytes that survived demyelination, but instead increased yet further the mistargeting of myelin by these cells (Figure 3D and I-J).…”