Rap1 is involved in the signal transduction of myelin-associated glycoprotein

Abstract

Myelin-associated glycoprotein (MAG) is a well-characterized axon growth inhibitor in the adult vertebrate nervous system. Several signals that play roles in inhibiting axon growth have been identified. Here, we report that soluble MAG induces activation of Rap1 in postnatal cerebellar granule neurons (CGNs) and dorsal root ganglion (DRG) neurons. The p75 receptor associates with activated Rap1 and is internalized in response to MAG. After MAG is applied to the distal axons of the sciatic nerves, the activated Rap1, internalized p75 receptor, and MAG are retrogradely trafficked via axons to the cell bodies of the DRG neurons. Rap1 activity is required for survival of the DRG neurons as well as CGNs when treated with MAG. Myelin-associated glycoprotein (MAG) is a member of the I-type lectin subgroup of the immunoglobulin (Ig) gene superfamily and is expressed exclusively by myelinating cells where it is enriched in the adaxonal membrane of the myelin internode. MAG inhibits neurite outgrowth from the adult dorsal root ganglion (DRG) and the postnatal ages of the cerebellar, retinal, spinal, hippocampal, and superior cervical ganglion neurons. 1,2 To date, two additional neurite growth inhibitors that are expressed by oligodendrocytes and myelinated fiber tracts have been identified. 3 These are Nogo and oligodendrocyte-myelin glycoprotein. All these proteins act on neurons through the Nogo receptor complex. This is a trimolecular complex comprising the Nogo receptor, Lingo-1, and p75/Troy. 4 A key intracellular effector for neurite growth inhibitory signaling by myelin was previously shown to be the small guanine nucleoside triphosphatase, RhoA. In its active GTP-bound form, RhoA rigidifies the actin cytoskeleton, thereby inhibiting axon elongation and mediating growth cone collapse. RhoA is activated by these proteins through a p75-dependent mechanism, thus inhibiting neurite outgrowth from the postnatal sensory neurons and cerebellar neurons. 5,6 It was also demonstrated that conventional protein kinase C (PKC), including PKC-a, -b, and -g, was activated by the neurite growth inhibitory proteins, and the inhibition of conventional PKC eliminated the effect of these proteins on neurite outgrowth. 7,8 In addition, phosphorylation of the epidermal growth factor (EGF) receptor is triggered by these myelin-derived inhibitors and is necessary for the inhibitory effect. 9 These multiple signals are responsible for the effects of the myelin-derived inhibitors at least in vitro.In addition to the role of MAG in axon regeneration, experiments with MAG-deficient mice implicate this protein in regulating axonal caliber and the levels of neurofilament spacing in mature myelinated fibers. 10 MAG is suggested to modulate the maturation and viability of myelinated axons. These findings suggest the diverse functions of MAG in the nervous system.In the course of identifying signals downstream of MAG, we found that Rap1 is activated in response to soluble MAG. Rap1 is a member of the Ras family of small guanine nucleotidebinding ...

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