Abstract
Myelin-associated glycoprotein (MAG) is a sialic acid binding Ig-like lectin (Siglec) which has been characterized as potent myelin-derived inhibitor of neurite outgrowth. Two members of the Nogo-receptor (NgR) family, NgR1 and NgR2, have been identified as neuronal binding proteins of MAG. In addition, gangliosides have been proposed to bind to and confer the inhibitory activity of MAG on neurons. In this study, we investigated the individual contribution of NgRs and gangliosides to MAG-mediated inhibition of sensory neurons derived from dorsal root ganglia (DRG) of ngr1, ngr2 or ngr1/ngr2 deletion mutants. We found no disinhibition of neurite growth in the absence of either NgR1 or NgR2. Sensory neurons deficient for both NgR proteins displayed only a moderate reduction of MAG-mediated inhibition of neurite growth. If treated with Vibrio cholerae neuraminidase (VCN), inhibition by MAG is further attenuated but still not annulled. Thus, disrupting all known protein and ganglioside receptors for MAG in sensory neurons does not fully abolish its inhibitory activity pointing to the existence of as yet unidentified receptors for MAG. Moreover, by employing a variety of protein mutants, we identified the Ig-like domains 4 or 5 of MAG as necessary and sufficient for growth arrest, whereas abolishing MAG's ability to bind to sialic acid did not interfere with its inhibitory activity. These findings provide new insights into the inhibitory function of MAG and suggest similarities but also major differences in MAG inhibition between sensory and central nervous system (CNS) neurons.
Highlights
Myelin-associated glycoprotein (MAG)/sialic acid binding Ig-like lectin (Siglec)-4a is expressed in myelinating glia of the central and peripheral nervous system (PNS)
Expression of NgR1 or other known receptor components conferring MAG responsiveness such as p75NTR or TROY/TAJ were unaltered in cultured sensory neurons
Because recent findings suggest that gangliosides, notably GT1b and GD1a, can act as functional MAG receptors on neurons in a sialic acid dependent manner [21,22,23,24], we examined whether disrupting gangliosides on ngr1/ngr2 double null neurons would result in full release of MAG inhibition
Summary
MAG/Siglec-4a is expressed in myelinating glia of the central and peripheral nervous system (PNS) It is a member of the Siglecs [1], a sialic acid binding subgroup of the immunoglobulinsuperfamily (IgSF). Two neuronal proteins of the Nogo-receptor family, NgR1 and NgR2, have been shown to bind MAG with similar affinity and to confer growth arrest [11,12,13]. Both receptors are glycosylphosphatidylinositollinked proteins and require partner proteins for signal transduction. Albeit slightly less inhibited on MOGMAG Ig5 (Fig. 5D), suggesting that the Ig-like domain 5 of MAG has somewhat weaker inhibitory potential than the Ig-like domain 4, at least in the structural context of the MOG molecule
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