Growth-blocking MAG (green) binds to the neurotrophin receptor p75NTR (red).

When adult neurons are injured, myelin-associated glycoprotein (MAG) triggers signals to block the regrowth of axons, a process that is intensely frustrating to patients and researchers hoping to treat such injuries. On page 565, Yamashita et al. identify a receptor complex responsible for transducing this signal, elucidate part of the associated intracellular signaling pathway, and uncover a novel molecular interaction that may help explain the diverse activities of a neurotrophin receptor.

MAG signaling is known to inhibit axonal regrowth after injury, but the MAG receptor on neurons remained unknown. By analyzing neurons from wild-type and mutant mice, the authors discovered that p75NTR, a glycoprotein on the surface of many types of neurons, transduces the MAG signal. Since p75NTR also binds to neurotrophins, which promote axonal outgrowth, the same receptor seems to be capable of transducing both growth and inhibitory signals.

Rather than binding directly to p75NTR, MAG interacts with a complex of p75NTR and the ganglioside GT1b. This is the first time a ganglioside has been shown to act as a coreceptor, a finding that may set a precedent for future analysis of these molecules. MAG binding to the complex activates RhoA, which has previously been shown to inhibit neurite extension. The results suggest that GT1b acts primarily as a binding partner, whereas p75NTR is a signal transducing element for MAG.

Since gangliosides are found in lipid rafts, an intriguing possibility is that p75NTR interacts with different factors in a raft to transduce opposite types of signals, depending on its interaction with MAG or neurotrophins. Molecules that target specific components of these pathways might be able to induce desired growth patterns in injured neurons. ▪