Glia unglued: How signals from the extracellular matrix regulate the development of myelinating glia

Abstract

The health and function of the nervous system relies on glial cells that ensheath neuronal axons with a specialized plasma membrane termed myelin. The molecular mechanisms by which glial cells target and enwrap axons with myelin are only beginning to be elucidated, yet several studies have implicated extracellular matrix proteins and their receptors as being important extrinsic regulators. This review provides an overview of the extracellular matrix proteins and their receptors that regulate multiple steps in the cellular development of Schwann cells and oligodendrocytes, the myelinating glia of the PNS and CNS, respectively, as well as in the construction and maintenance of the myelin sheath itself. The first part describes the relevant cellular events that are influenced by particular extracellular matrix proteins and receptors, including laminins, collagens, integrins, and dystroglycan. The second part describes the signaling pathways and effector molecules that have been demonstrated to be downstream of Schwann cell and oligodendroglial extracellular matrix receptors, including FAK, small Rho GTPases, ILK, and the PI3K/Akt pathway, and the roles that have been ascribed to these signaling mediators. Throughout, we emphasize the concept of extracellular matrix proteins as environmental sensors that act to integrate, or match, cellular responses, in particular to those downstream of growth factors, to appropriate matrix attachment.

Integrins and the extracellular matrix: Key mediators of development and regeneration of the sensory nervous system

“…In the peripheral nerves of laminin a2 mutant mice, the basement membrane is also disrupted, axons have reduced Schwann cell ensheathment and myelination; however, the phenotype is perhaps relatively mild, as there is a compensatory increase in laminins a4 and a1 isoforms (Patton et al, 1997;Previtali et al, 2003b). The importance of laminin-integrin interaction in Schwann cells in radial sorting, axonal maturation and myelination is described in further detail by Colognato and Tzvetanova (2011). Sensory axon terminals in the skin associate with laminins-111, -121 (Dubovy et al, 1999) and -332 (Reinisch and Tschachler, 2005).…”

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…ErbB receptor activation triggers multiple second messengers in Schwann cells (for details see also Colognato and Tzvetanova, 2011; Taveggia et al, 2010). Activation of the PI3K/Akt/mTOR pathway (Maurel and Salzer, 2000; Taveggia et al, 2005), the Shp2/Erk/MAPK pathway (Grossmann et al, 2009; Newbern et al, 2011), and the PLC/Calcineurin/NFAT pathway (Kao et al, 2009) are all critical for myelination (Figure 1).…”

Peripheral nerve ultrasound in pediatric Charcot-Marie-Tooth disease type 1A

“…Extracellular matrix molecules (some of which are synthesised by Schwann cells) have a role in axonal growth and Schwann cell proliferation and differentiation. 17,18 Abnormalities in vitronectin and tenascin expression were noted in sural nerve biopsies of individuals with CMT type 1 (half of whom had genetically confirmed CMT1A). 19 Vitronectin has been shown to inhibit axonal and Schwann cell regeneration.…”