Nerve Regeneration: Regrowth Stumped by Shared Receptor Dispatch

Unlike peripheral nervous system (PNS) axons, severed central nervous system (CNS) axons are unable to regenerate. Why do CNS and PNS axons differ so dramatically in their regenerative abilities? Differences in CNS and PNS glial cells appear to be crucial, as some CNS axons are able to regenerate through a peripheral nerve graft [1]. Axons are tightly wrapped by myelin membrane produced by oligodendrocytes in the CNS and Schwann cells in the PNS. Following axonal injury in the PNS, myelin is rapidly cleared by macrophages as the axons degenerate in a process known as Wallerian degeneration. In contrast, myelin is cleared much more slowly after CNS injury. This difference suggests that CNS myelin strongly inhibits regenerating axons, a possibility that was directly confirmed in elegant experiments by Martin Schwab and his colleagues [2]. An important first step towards identifying myelin inhibitors of axon regeneration was taken many years ago with the development of an anti-CNS myelin monoclonal antibody, IN-1, which promotes CNS regeneration and a limited degree of functional recovery in animal models [2]. Only in the last few years, however, have researchers begun to elucidate the key inhibitors and their receptors, uncovering a few surprises along the way. The target of the IN-1 antibody turned out to be Nogo, a reticulon homolog with three isoforms: Nogo-A is expressed primarily in oligodendrocytes, and the other two isoforms are more widely distributed ([reviewed in [3]). Interestingly, Nogo-A has two separate domains that can inhibit growing axons: the amino-terminal portion (Amino-Nogo), which is unique to Nogo-A, and a 66 amino acid peptide (Nogo-66) located between the two transmembrane regions, which is common to all isoforms. How does Nogo inhibit regenerating axons? The functional receptor for Nogo-66, NgR, is a 473 amino acid protein with an attached glycosylphosphatidylinositol (GPI) lipid. This GPI linkage serves to anchor the protein to the outer surface of the cell membrane, where it can interact with its ligand. Binding studies and the effects of ectopic expression both confirmed that this protein is the functional receptor for Nogo-66 [4]. The expression patterns of Nogo and NgR are consistent with the interactions of these proteins at points of contact between axons and myelin, as well as at synapses [5]. It is unlikely, however, that NgR works alone: its lack of a transmembrane region implies the presence of an as yet unidentified transmembrane coreceptor that transduces the inhibitory signal. These new findings have already led to efforts to develop drugs that enhance CNS regeneration. By analyzing small peptide fragments of Nogo-66, Strittmatter and colleagues [6] found that, although residues 1–31 of Nogo-66 bind with high affinity to NgR, only a peptide containing residues 31–55 inhibits axon outgrowth. On the basis of these results, they developed a competitive antagonist peptide, termed NEP1-40 for ‘Nogo extracellular peptide residues 1–40’, which specifically blocks Nogo-66, but not Amino-Nogo, activity [6]. The delivery of NEP1-40 into an injured rat spinal cord produces significant axon regrowth and a modest but noteworthy promotion of locomotor recovery. This finding supports the view that NgR plays an important role in CNS regenerative failure and is an encouraging target for new therapeutics. While Nogo has attracted much of the spotlight of late, additional inhibitory myelin proteins are known. One of these, myelin-associated glycoprotein (MAG), shares with Nogo the interesting property that it inhibits postnatal and adult, but not embryonic, neurons. MAG binds to a sialic acid-bearing glycosphingolipid called ganglioside GT1b and closely related gangliosides on the neuronal surface. This ganglioside has been suspected of helping to form a MAG receptor, because clustering of GT1b by antibody complexes is sufficient to inhibit neurite outgrowth by activating a Rho kinase [7,8], but it has been unclear how a ganglioside could help to transmit a signal across the plasma membrane. Unexpectedly, the ganglioside GT1b turns out to associate with the neurotrophin receptor p75 to form a MAG receptor complex which transmits an inhibitory signal via the small GTPase Rho [9]. As no inhibitory effect of MAG is seen in the absence of p75, this complex appears to be necessary and sufficient to mediate MAG’s inhibitory effects. In striking contrast to this report, a mutant MAG that is unable to bind to gangliosides still inhibits neurite outgrowth when expressed on Schwann cells, implying the presence of an additional MAG receptor [10]. Intriguing new studies have revealed that the Nogo-66 receptor NgR fits the bill and, moreover, is itself necessary and sufficient to mediate MAG’s inhibitory actions [11,12]. These latest findings show that MAG binding to NgR is independent of GT1b, that dominantnegative forms of NgR block MAG activity, and that NgR expression confers both MAG and Nogo-66 responsiveness on embryonic neurons. Importantly, however, the NgR antagonist peptide NEP1-40 does not interfere with MAG’s inhibitory activity [12], suggesting that additional functional recovery may be achieved by improved antagonists. Current Biology, Vol. 12, R654–R656, October 1, 2002, ©2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)01159-4