Abstract
Myelin-Associated Glycoprotein (MAG), a major inhibitor of axonal growth, is a member of the immunoglobulin (Ig) super-family. Importantly, MAG (also known as Siglec-4) is a member of the Siglec family of proteins (sialic acid-binding, immunoglobulin-like lectins), MAG binds to complex gangliosides, specifically GD1a and/or GT1b. Therefore, it has been proposed as neuronal receptors for MAG inhibitory effect of axonal growth. Previously, we showed that MAG binds sialic acid through domain 1 at Arg118 and is able to inhibit axonal growth through domain 5. We developed a neurite outgrowth (NOG) assay, in which both wild type MAG and mutated MAG (MAG Arg118) are expressed on cells. In addition we also developed a soluble form NOG in which we utilized soluble MAG-Fc and mutated MAG (Arg118-Fc). Only MAG-Fc is able to inhibit NOG, but not mutated MAG (Arg118)-Fc that has been mutated at its sialic acid binding site. However, both forms of membrane bound MAG- and MAG (Arg118)- expressing cells still inhibit NOG. Here, we review various results from different groups regarding MAG’s inhibition of axonal growth. Also, we propose a model in which the sialic acid binding is not necessary for the inhibition induced by the membrane form of MAG, but it is necessary for the soluble form of MAG. This finding highlights the importance of understanding the different mechanisms by which MAG inhibits NOG in both the soluble fragmented form and the membrane-bound form in myelin debris following CNS damage.
Highlights
Myelin-associated glycoprotein (MAG), a member of the immunoglobulin (Ig) superfamily, contains five Ig-like domains in its extracellular sequences, a single transmembrane domain, and a short cytoplasmic domain (Figure 1A; Lai et al, 1987a,b; Salzer et al, 1987, 1990)
Myelin-Associated Glycoprotein (MAG) binds sialic acid at Arg118, which is located in domain 1 of MAG, distant from the inhibitory site in domain 5
Soluble MAG requires sialic acid binding for inhibition of neurite outgrowth (NOG)
Summary
Myelin-associated glycoprotein (MAG), a member of the immunoglobulin (Ig) superfamily, contains five Ig-like domains in its extracellular sequences, a single transmembrane domain, and a short cytoplasmic domain (Figure 1A; Lai et al, 1987a,b; Salzer et al, 1987, 1990). MAG was first reported as a sialic acid binding protein that interacts with the complex gangliosides GT1b and GD1a (Vinson et al, 2001). MAG was shown to bind and signal through β-1 integrin (Goh et al, 2008). PTEN, a lipid phosphatase that activates AKT, was found to mediate the MAG inhibitory signal, suggesting the existence of other, as yet unknown, receptors (Perdigoto et al, 2011). Discovering MAG receptors is critical for identifying therapeutic targets for promoting axonal regeneration, and it is important to clarify the role of gangliosides in MAG-induced inhibition of NOG. We focus on the relationship between MAG and sialic acid in gangliosides, please see a recent extensive review of sialic acids (Schnaar et al, 2014)
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