Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling

Abstract

In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.

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.…”

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

“…To determine to what extent EphA receptors expressed on oligodendrocytes (Linneberg et al, 2015) might be involved in inhibition of process extension, we cultured oligodendrocytes on PDL or ephrin-A1 substrates in the presence or absence of inhibitory peptides that specifically block the interaction with EphA2 or EphA4, respectively. Ephrin-A1 has no effect on the expression of markers of mature oligodendrocytes (mAG and MBP) (Figure 2a), but inhibits the morphological differentiation of oligodendrocytes F IGURE 4.…”

“…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).…”

“…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.…”

Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling

“…Astrocytes (16,17) and CNS white matter (18)(19)(20) inhibit SC migration within CNS, pointing out that multiple CNS components can alter this process. Among the molecules involved in various cell type segregation and guidance within the CNS, the Eph/ephrin family has been implicated in both developmental (21,22) and 4 pathological conditions (23). In particular, EphrinB3, is expressed in myelin in brain and mouse spinal cord (24)(25)(26), and plays an important role in preventing neurite outgrowth (24), axonal regeneration (25) and oligodendrocyte progenitor differentiation (26).…”