Abstract
Multiple sclerosis is characterized by repeated demyelinating attacks of the central nervous system (CNS) white matter tracts. To tailor novel therapeutics to halt or reverse disease process, we require a better understanding of oligodendrocyte biology and of the molecular mechanisms that initiate myelination. Cell extrinsic mechanisms regulate CNS myelination through the interaction of extracellular matrix proteins and their transmembrane receptors. The engagement of one such receptor family, the integrins, initiates intracellular signaling cascades that lead to changes in cell phenotype. Oligodendrocytes express a diverse array of integrins, and the expression of these receptors is developmentally regulated. Integrin-mediated signaling is crucial to the proliferation, survival, and maturation of oligodendrocytes through the activation of downstream signaling pathways involved in cytoskeletal remodeling. Here, we review the current understanding of this important signaling axis and its role in oligodendrocyte biology and ultimately in the myelination of axons within the CNS.
Highlights
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) resulting in physical and cognitive disabilities
The extracellular and transmembrane domains of α5-integrin were fused with the cytoplasmic tail of the α6-integrin subunit. Expression of this hybrid α5/α6-integrin subunit in oligodendrocytes increased survival during concurrent FN adhesion and platelet-derived growth factor (PDGF) administration, a response normally observed on LN2 substrate via α6β1-integrin receptors. These results indicate that the survival-promoting events occurring via concurrent LN2 ligation and PDGF administration are mediated via α6β1-integrin receptors
While this study demonstrates a relationship between integrin and PDGF signaling, it does not explain how integrins and GF receptors (GFRs) interact
Summary
Multiple sclerosis (MS) is an inflammatory disease of the CNS resulting in physical and cognitive disabilities. OPCs have simple morphology relative to their differentiated state, bearing only a few processes. These cells are highly responsive to soluble growth factors (GFs), which promotes their proliferation/survival [3]. The molecular events underlying oligodendrocyte proliferation, survival, and maturation are poorly understood, yet knowledge of these processes is of great value for the development of therapeutics for demyelinating diseases like MS. Integrin-based amplification of GF-signaling depends on common proliferation/survival pathways involving phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. PI3Ks are a family of ubiquitously expressed proteins responsible for a broad variety of cellular functions including signal transduction, migration, proliferation, survival, and cytoskeletal reorganization [4]. Oligodendrocyte differentiation and maturation are impacted by integrin signaling, involving proteins such as Fyn kinase. The goal of the present paper is to outline the importance of integrin signaling in various aspects of oligodendrocyte biology
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