From Cell Death to Neuronal Regeneration, Effects of the p75 Neurotrophin Receptor Depend on Interactions with Partner Subunits

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Science's STKE  01 Jun 2004:
Vol. 2004, Issue 235, pp. pe24
DOI: 10.1126/stke.2352004pe24


In the adult mammalian central nervous system (CNS), growth of neuronal fibers is actively inhibited by myelin. The proteins myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgP), and Nogo-66 have been identified as inhibitory components present in CNS myelin. All three proteins exert their inhibitory activity by binding to a neuronal receptor complex containing the Nogo-66 receptor (NgR) and the neurotrophin (NT) receptor p75NTR. In their recent publication, Mi et al. identify the novel protein Lingo-1 as an interactor of p75NTR and NgR. The Lingo-1-NgR-p75NTR complex is shown to confer the inhibitory effects on nerve cell regeneration of Nogo-66, OMgP, and MAG by activating the small guanosine triphosphatase (GTPase) RhoA. Together with the recent finding that p75NTR interacts with the transmembrane protein sortilin to form a different receptor complex with cell death-promoting activity, the results of Mi et al. indicate that p75NTR exerts its diverse cellular functions by associating with function-specific co-receptors.

p75NTR, a member of the tumor necrosis factor receptor (TNFR) superfamily, was isolated almost 20 years ago as a binding protein for nerve growth factor (NGF). The early isolation of what was then called the "NGF receptor" was followed by a time of increasing frustration, as it became progressively clear that neither the expression pattern of p75NTR nor its activation by NGF would explain some of the most characteristic activities of NGF, including the prevention of neuronal cell death. The discovery of the receptor tyrosine kinase TrkA as a readily identifiable signaling receptor for NGF seemed to untangle many of these controversies, and p75NTR was largely relegated to the role of modulating and modifying TrkA signaling. Although this function of p75NTR continues to be an important area of investigation, our perspective on p75 NTR was recently revolutionized when it became clear that p75NTR can cooperate with several different protein interaction partners to form multimeric receptor complexes (Fig. 1). Consequently, p75NTR is now implicated, besides its role in neurotrophic signaling, in a diverse array of cellular responses, including apoptosis, neurite outgrowth, and myelination (1, 2).

Fig. 1.

Models of actively signaling p75NTR receptor complexes. p75NTR, depicted in red, is a member of the TNFR superfamily and forms complexes with other proteins in the membrane of responsive cells. The formation of a complex between p75NTR and NgR is stimulated by binding of one of three different myelin-derived inhibitory protein ligands, OMgP, Nogo-66, or MAG. For signal transduction, the p75NTR-NgR complex requires Lingo-1, a novel transmembrane protein. The ternary complex might prevent regeneration of injured nerve fibers in the CNS through activation of RhoA. The recently discovered p75NTR-sortilin complex triggers cell death when activated by binding of the unprocessed precursor form of NGF. On oligodendrocytes, Rac is activated as a part of a p75NTR-dependent proapoptotic pathway. In complexes with the receptor tyrosine kinases of the Trk family, p75NTR acts as a modulatory receptor and increases binding affinity of the complex for specific NT ligands, whereas the binding of other ligands from the same family is reduced. In the downstream signaling pathways of the p75NTR-Trk complexes, a third small GTPase, Ras, plays an important role as a regulator of neuronal survival and differentiation.

Using a yeast two-hybrid screen, Barde and colleagues found in 1999 that p75NTR interacts with RhoA and constitutively stimulates RhoA activity when both proteins were overexpressed in nonneuronal cell lines (3). In neurons, the action of the Rho family of small guanosine triphosphatases (GTPases) on the actin cytoskeleton plays a major role in regulating axonal and dendritic growth (4). Hence, the potential of p75NTR to interfere with the activity of RhoA attracted attention when it became evident that myelin proteins such as Nogo-66, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgP) inhibit axonal growth at least in part through a Rho-dependent mechanism (5, 6). Although distinct in molecular structure, these three proteins bind to the same high-affinity binding molecule, the Nogo-66 receptor (NgR). Because NgR is glycosylphosphatidylinositol (GPI)-linked to the neuronal cell surface, its lack of a cytoplasmic domain suggested the participation of an interacting transmembrane receptor subunit to transduce the inhibitory signals intracellularly. Consistent with this model, NgR binds to the extracellular domain of p75NTR. Disruption of the interaction between NgR and p75NTR, either by NgR dominant-negative mutation or in cells from p75NTR knockout mice, renders cultured neurons unresponsive to myelin (7, 8). The current model of myelin-mediated signaling therefore suggests that ligand binding to NgR induces the direct interaction of NgR with p75NTR, which conveys the inhibitory signals intracellularly to RhoA (9). With the recent identification of the novel protein Lingo-1 as an additional component of the NgR-p75NTR receptor complex, Mi et al. (1) provide further insights into the mechanisms underlying myelin and p75NTR-mediated growth inhibition.

The structure of Lingo-1 is characterized by a pattern of 12 leucine-rich domains in the extracellular domain, followed by an Ig-like domain and a single membrane-spanning region. In its short intracellular domain, Lingo-1 lacks the characteristics of classic signal-transducing receptors. This indicates that Lingo-1 may function primarily as a modulator that requires additional molecules for signal transduction. The Lingo-1 gene is a member of a family of four related genetic loci and is highly conserved between mouse and man. The expression pattern of the Lingo-1 gene is intriguing. In the adult, it is restricted to the nervous system, with a rostrocaudal gradient of expression. Its developmental regulation peaks at early postnatal periods, when most of the connections between nerve cells are formed. Importantly, Lingo-1 gene expression is increased when adult nerve cells in the spinal cord are exposed to traumatic injuries.

Mi et al. convincingly demonstrate that Lingo-1 forms a complex with two proteins in the plasma membrane. Like p75NTR, it associates with the NgR. However, the complex of Lingo-1 and NgR, when overexpressed in nonneuronal cell lines, is incapable of transducing a signal to Rho. The authors went on to show that Lingo-1 physically binds to p75NTR. The binding of Lingo-1 to either p75NTR or NgR can occur independently and simultaneously. In functional experiments with nonneuronal cell lines, only the expression of both p75NTR and NgR together with Lingo-1 endowed cells with the capacity to activate Rho in the presence of the myelin-derived ligand OMgP. This strongly supports the idea of the formation of a ternary receptor complex consisting of all three proteins that is required to render cells fully responsive to myelin-associated inhibitors. Consistent with these biochemical findings, the three proteins are all expressed in neurons, which suggests that the newly discovered receptor complex might indeed occur naturally on the surface of nerve cells.

In cultured neurons, the activity of the Lingo-1-NgR-p75NTR receptor complex can be modulated. To show this, Mi et al. measured the length of nerve cell processes rather than Rho activity. When neurons were transfected with a DNA construct encoding a soluble and truncated from of Lingo-1 and were subsequently treated with the inhibitory ligands OMgP or Nogo-66, these cells had longer cellular processes than did control cells. Thus, this soluble Lingo-1 apparently acts as a partial antagonist. A similar effect was observed when a different mutant Lingo-1 protein was expressed that retains the transmembrane domain but lacks the intracellular domain of the wild-type receptor. Consequently, the inconspicuous intracellular domain of Lingo-1 appears to be of functional relevance for the protein.

The findings of Mi et al. take us a big step closer to an understanding of the signaling mechanisms that actively and specifically prevent nerve fibers from growing past the site of an injury in the adult central nervous system (CNS). The identification of the trimeric receptor consisting of Lingo-1, NgR, and p75NTR gives room for new ideas about therapeutic interventions that might favor regrowth of neurons by interfering with the assembly of the complex.

One important open question now is whether the presence of the ternary Lingo-1-NgR-p75NTR complex is essential for myelin-induced growth inhibition in vivo, or whether alternative mechanisms are present in the injured CNS. This question becomes pressing in light of recent data showing that in mice the regeneration of fibers in the corticospinal tract after injury is not improved after expression of a targeted mutation in the p75NTR gene (10). At present, it is also still unclear whether p75NTR is prominently expressed in injured adult neurons. Mi et al. show that Lingo-1 is expressed by many neurons projecting over long distances in the adult CNS, and its expression is increased in injured axons. Therefore, Lingo-1 might be crucially involved in the sensitization of neurons to inhibitory signals.

There is increasing evidence that p75NTR and NgR do not act as central components of receptors for inhibitory factors other than OMgP, MAG, and Nogo-66 (9, 11). It will be interesting to learn whether Lingo-1 can form complexes with other receptors that mediate axonal inhibition and bind ligands such as chondroitin-sulfate proteoglycans, the central inhibitory domain of Nogo-A, or even semaphorins.

A common feature of the signaling of all identified inhibitors is their regulation of Rho. The involvement of a RhoA-dependent signaling pathway in the inhibition of axonal regeneration in vivo is supported by studies in which RhoA is inhibited with the bacterial enzyme C3, or in which activity of the important downstream Rho effector Rho-kinase (ROCK) is inhibited. These treatments lead to regeneration of injured fiber tracts and functional recovery (12). In the experiments of Mi et al., RhoA is activated only in cells that express p75NTR together with NgR and Lingo-1 and in the presence of the ligands OMgP, MAG, or Nogo-66. The precise mechanism of Lingo-1-NgR-p75NTR mediated RhoA activation, however, remains to be determined. According to a previously suggested model, NgR-p75NTR activation leads to the binding of the Rho-GTP dissociation inhibitor (Rho-GDI) to p75NTR, thus enabling RhoA to become activated (13).

The findings that link p75NTR to axonal inhibition and activation of Rho should not be discussed separately from a second major advance in research on p75NTR. In parallel to its role in axonal inhibition, the same receptor is attracting increasing attention as a regulator of apoptosis. Besides its participation in the complex with NgR and Lingo-1, p75NTR also forms a complex with the transmembrane protein sortilin. When this receptor complex is activated, the cells that display it on their surface usually die (14). The death-promoting p75NTR-sortilin complex is activated by an unusual ligand, the pro-form of the prototypic neurotrophin NGF. ProNGF is the primary translational product of NGF transcripts and is almost twice the size of NGF. Until recently, it was considered merely a biosynthetic precursor of mature NGF, which was constitutively cleaved off the pro-form by metalloproteases before secretion. However, proNGF that escapes proteolytic cleavage can be secreted and becomes available for receptor interactions (15). The production and secretion of proNGF appear to be linked to noxious challenges to the nervous system. ProNGF binds with high affinity to the complex of p75NTR and sortilin to promote apoptotic cell death (14). In oligodendrocytes, the p75NTR signaling pathway emanating from the proapoptotic receptor complex appears to be independent of the activation of Rho and leads to activation of another small GTPase, Rac, and the proapoptotic c-Jun N-terminal kinase (JNK) cascade (16). In spinal cord lesions, the predominant site of proNGF-induced death seems to be in glial cells, especially in cells of the oligodendrocyte lineage. Thus, p75NTR-mediated death of oligodendrocytes might also play an important role in CNS lesions (17). Finally, a third type of complex combines p75NTR with yet another group of transmembrane receptors. P75NTR physically interacts with all three members of the Trk family of receptor tyrosine kinases (18). One of the important functions of these NT receptors is to antagonize the p75NTR proapoptotic pathway (19).

Together, these findings draw a complex picture of p75NTR. The molecule is involved in multiple cellular functions and participates in the formation of several distinct multimeric transmembrane receptor complexes. It is likely that the different p75NTR receptor complexes coexist on neurons and oligodendrocytes, where they may be linked by biochemical equilibria and signal independently, synergistically, or antagonistically. Most of these findings are very recent and it is still too early to attempt a synoptic interpretation. Unfortunately, this has led to a situation in which the different classes of p75NTR complexes are frequently discussed separately, to the exclusion of developments in the other p75NTR fields. The effects of interfering with one receptor complex on the functions of the others remains to be established. One example of the physiologic relevance of such considerations might, in fact, be the modulation of Rho activity. As we have discussed, the binding of the myelin inhibitors MAG, Nogo-66, and OMgP leads to activation of RhoA through the Lingo-1-NgR-p75NTR trimeric receptor. However, binding of NGF to p75NTR can also inactivate Rho, suggesting a mechanism by which NGF stimulates neurite formation through p75NTR (3). Thus, p75NTR might well stimulate neurite elongation if bound to NGF but inhibit elongation when bound by Nogo-66, MAG, or OMgP.

The biological response of a cell expressing p75NTR may depend on the precise composition of its receptor complement in its membrane, both in quantitative and qualitative terms, in combination with kinetic parameters that determine the formation of active signaling entities. The key to a profound understanding of the role of p75NTR in regeneration, cell death, and cell survival, therefore, resides not only in the analysis of the molecular composition of the different p75NTR-containing receptor complexes, as was most elegantly achieved for Lingo-1 by Mi et al. It appears equally important to study the cross talk between the different receptor complexes at the membrane and in their downstream signaling pathways.


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