Identification of dystroglycan as a second laminin receptor in oligodendrocytes, with a role in myelination

Abstract

2Developmental abnormalities of myelination are observed in the brains of laminin-deficient humans and mice. The mechanisms by which these defects occur remain unknown. It has been proposed that, given their central role in mediating extracellular matrix (ECM) interactions, integrin receptors are likely to be involved. However, it is a non-integrin ECM receptor, dystroglycan, that provides the key linkage between the dystrophin-glycoprotein complex (DGC) and laminin in skeletal muscle basal lamina, such that disruption of this bridge results in muscular dystrophy. In addition, the loss of dystroglycan from Schwann cells causes myelin instability and disorganization of the nodes of Ranvier. To date, it is unknown whether dystroglycan plays a role during central nervous system (CNS) myelination. Here, we report that the myelinating glia of the CNS, oligodendrocytes, express and use dystroglycan receptors to regulate myelin formation. In the absence of normal dystroglycan expression, primary oligodendrocytes showed substantial deficits in their ability to differentiate and to produce normal levels of myelin-specific proteins. After blocking the function of dystroglycan receptors, oligodendrocytes failed both to produce complex myelin membrane sheets and to initiate myelinating segments when co-cultured with dorsal root ganglion neurons. By contrast, enhanced oligodendrocyte survival in response to the ECM, in conjunction with growth factors, was dependent on interactions with beta-1 integrins and did not require dystroglycan. Together, these results indicate that laminins are likely to regulate CNS myelination by interacting with both integrin receptors and dystroglycan receptors, and that oligodendrocyte dystroglycan receptors may have a specific role in regulating terminal stages of myelination, such as myelin membrane production, growth, or stability.

Modulation of cell spreading and cell-substrate adhesion dynamics by dystroglycan

“…A dystroglycanvinexin-vinculin complex could also link dystroglycan to integrins. Links between dystroglycan and integrin adhesion systems have been implied or hypothesised by others, both at a signalling level and a mechano-structural level (Ferletta et al, 2003;Jones et al, 2005;Colognato et al, 2007;Peng et al, 2008). Our preliminary data also suggest that vinculin-containing adhesion structures can form on E3 laminin, which is a non-integrin-engaging ligand, presumably mediated by dystroglycan.…”

β1 integrins are required for normal CNS myelination and promote AKT-dependent myelin outgrowth

“…Consistent with this model, the loss of β1 integrins in oligodendrocytes affected AKT activation. A second laminin receptor, dystroglycan, which also promotes myelin membrane outgrowth in vitro (Colognato et al, 2007), did not affect AKT activation, indicating that there is a specific link between AKT and β1 integrins. Furthermore, defects in myelin membrane outgrowth in β1-deficient oligodendrocytes were rescued upon expression of constitutively active AKT or by modulating endogenous AKT activity levels with a PTEN inhibitor.…”

“…Oligodendrocyte progenitors were isolated and cultured following published procedures (Colognato et al, 2007;Colognato et al, 2004), with the addition of a panning step to remove microglia (Cahoy et al, 2008). Briefly, oligodendrocyte progenitor cells (OPCs) were isolated from 10-days-invitro (DIV) mixed glial cultures using a 20-hour mechanical dissociation followed by a 30-minute differential adhesion step with uncoated petri dishes.…”

The Development of a ɛ-Polycaprolactone Scaffold for Central Nervous System Repair

“…These ECM proteins have been shown to enhance myelination when in direct contact with neurons plated on glass coverslips. 32,33 PLL-coated PCl substrates were used for comparison (Fig. 4E).…”