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¹ Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
² Core Research for Evolutional Science and Technology (CREST), Kawaguchi 332-0012, Japan

Address correspondence to Toshihide Yamashita, Dept. of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-68793221. Fax: 81-6-68793229. E-mail: tyama{at}anat2.med.osaka-u.ac.jp

	Abstract

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Myelin-associated glycoprotein (MAG) is a potent inhibitor of neurite outgrowth from a variety of neurons. The receptor for MAG or signals that elicit morphological changes in neurons remained to be established. Here we show that the neurotrophin receptor p75 (p75^NTR) is the signal transducing element for MAG. Adult dorsal root ganglion neurons or postnatal cerebellar neurons from mice carrying a mutation in the p75^NTR gene are insensitive to MAG with regard to neurite outgrowth. MAG activates small GTPase RhoA, leading to retarded outgrowth when p75^NTR is present. Colocalization of p75^NTR and MAG binding is seen in neurons. Ganglioside GT1b, which is one of the binding partners of MAG, specifically associates with p75^NTR. Thus, p75^NTR and GT1b may form a receptor complex for MAG to transmit the inhibitory signals in neurons.

Key Words: p75; neurotrophin; myelin-associated glycoprotein; Rho; ganglioside

	Introduction

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The neurotrophin receptor p75 (p75^NTR)^* is a membrane glycoprotein that binds to all neurotrophins identified so far. Motor neurons in the spinal cord, most sympathetic and sensory neurons in the peripheral nervous system, and cerebellar Purkinje cells and retinal ganglion cells all express p75^NTR at high levels during the outgrowth of axons (Buck et al., 1987; Ernfors et al., 1988; Yan and Johnson, 1988; Large et al., 1989; von Bartheld et al., 1991). In dendrite-bearing neurons, p75^NTR is also expressed during the time of dendritic arborization. Some neurons markedly up-regulate p75^NTR after lesion or seizure (Ernfors et al., 1989; Roux et al., 1999). It was shown recently that the neurotrophin binding to p75^NTR promoted axonal outgrowth of neurons and inactivated small GTPase RhoA (Yamashita et al., 1999). The link between p75^NTR and RhoA seems to be functionally relevant, since the modulation of neurite outgrowth in p75^NTR-expressing neurons by neurotrophins mimics the results obtained after RhoA inactivation.

Myelin-associated glycoprotein (MAG) is a well-characterized component of both the central nervous system and the peripheral nervous system myelin and is a potent inhibitor of axonal regeneration (McKerracher et al., 1994; Mukhopadhyay et al., 1994). It inhibits axonal outgrowth from adult dorsal root ganglion (DRG) and in postnatal ages of cerebellar, retinal, spinal, hippocampal, and superior cervical ganglion neurons. Although the molecular mechanism of action of MAG on neurons or the receptor that transmits the signals remained to be established, neurite growth inhibition by MAG is blocked if neurons are exposed to neurotrophins before encountering the inhibitor (Cai et al., 1999). We attempted to ask if p75^NTR had some roles in transducing the inhibitory signals of MAG in neurons. The results we obtained were surprising, since p75^NTR itself turned out to be a signal transducing element for MAG and neurotrophins. Association of p75^NTR with ganglioside GT1b is also shown to provide a possible link between MAG and p75^NTR.

	Results and discussion

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Inhibition of neurite outgrowth is dependent on p75^NTR
We first asked if p75^NTR was associated with the effects of MAG on neurons. Neurite outgrowth of adult DRG neurons from mice carrying a mutation in the p75^NTR gene (Lee et al., 1992) or wild-type mice was examined. A soluble chimeric form of MAG, consisting of the extracellular domain of MAG fused to the Fc region of human IgG (MAG–Fc), was used. It was shown that soluble MAG, released in abundance from myelin and found in vivo, and MAG–Fc could potently inhibit axonal growth (Tang et al., 1997a,b). We compared the neurite length between MAG-treated and MAG-untreated neurons. MAG–Fc at the concentration of 25 µg/ml inhibited neurite outgrowth of DRG neurons from adult wild-type mice (Fig. 1, A and B). Fc had no effect on the neurons (unpublished data). Interestingly, the inhibitory effect of MAG could not be observed in DRG neurons from adult mice carrying a mutation in the p75^NTR gene. Exactly the same results were obtained whether total process outgrowth or length of the longest neurite was measured (unpublished data).

View larger version (28K): [in this window] [in a new window]   Figure 1. The effects of MAG on neurons are dependent on p75NTR. (A) Dissociated DRG neurons were incubated for 24 h with or without MAG–Fc and then immunostained with monoclonal antibody (TuJ1) recognizing the neuron-specific ß–tubulin III protein. p75(+/+), wild type; p75(-/-), mice carrying a mutation in the p75NTR gene. (B) Mean length of the longest neurite per neuron. Data are mean ± SEM. An asterisk indicates statistical significance (*p < 0.01, Student's t test). (C) Mean length of the longest neurite per neuron. Dissociated cerebellar neurons were incubated for 24 h with or without MAG–Fc.

p75^NTR has been shown to be required for the inhibition of axonal growth and target innervation of peripheral neurons in vivo and in vitro (Kimpinski et al., 1999; Kohn et al., 1999) and for suppression of hyperinnervation of cholinergic neurons in vivo (Yeo et al. 1997). It was reported recently that the growth of sympathetic axons within the myelinated portions of the cerebellum was greater in NGF transgenic mice lacking expression of p75^NTR compared with those expressing p75^NTR in vivo (Walsh et al., 1999). It may be a relevant finding supporting our data, since neurons carrying a mutation in the p75^NTR gene are suggested to be refractory to inhibitory factors.

Signaling mechanisms of MAG on the neurons
Some neurons extend neurites rapidly when RhoA is inactivated, and neurite retraction occurs when RhoA is active (Davies, 2000). Previous study shows that inactivation of RhoA promoted axonal regeneration in vivo (Lehmann et al., 1999). Thus, to examine if activation of RhoA is necessary for modification of neurite outgrowth by MAG in our system, we employed the exoenzyme C3 transferase from Clostridium botulinum, which ADP ribosylates RhoA. The recombinant C3 transferase was introduced into the cytoplasm of DRG neurons by trituration. The C3 transferase completely abolished the effect of MAG on DRG neurons from wild-type mice (Fig. 2 A). These data are consistent with the previous report, suggesting RhoA is on the pathway of MAG signaling (Lehmann et al., 1999).

View larger version (57K): [in this window] [in a new window]   Figure 2. MAG activates RhoA through a p75NTR-dependent mechanism. (A) The effect of C3 transferase on MAG-treated DRG neurons from wild-type mice. Mean length of the longest neurite per neuron. Data are mean ± SEM. Asterisks indicate statistical significance (*p < 0.01, Student's t test). (B) Binding of MAG–Fc to 293 cells was visualized by incubation with an FITC-tagged anti–human IgG. (C) Affinity precipitation of RhoA in transfected 293 cells. MAG–Fc (25 µg/ml) elicits activation of RhoA only when 293 cells express p75NTR.

Regulation of RhoA activity when the proteins are artificially expressed may be difficult to detect in natural cells. Therefore, to see if RhoA activity is regulated by MAG in the cells expressing endogenous p75^NTR postnatal cerebellar granule neurons were used, since these neurons also are sensitive to MAG with regard to neurite outgrowth. Consistent with the observation in transfected 293 cells, MAG–Fc activates RhoA in cerebellar granule neurons from wild-type mice (P9), which express abundant p75^NTR (Fig. 3 A). This rapid activation was in contrast with the effect of NGF on the neurons, which is also mediated by p75^NTR, since they don't express trkA (Fig. 3 B). RhoA activity (Fig. 3 C) and the effect of MAG on neurite outgrowth (unpublished data) seem to be saturated by MAG at the concentration of 25 µg/ml. Activation of RhoA by MAG was lost in the neurons from mice carrying a mutation in the p75^NTR gene (Fig. 3 D). These data demonstrate that MAG activates RhoA by a p75^NTR-dependent mechanism, thus inhibiting neurite outgrowth of postnatal cerebellar granule neurons.

View larger version (31K): [in this window] [in a new window]   Figure 3. Affinity precipitation of RhoA in postnatal cerebellar neurons. (A) RhoA activity was increased after the addition of MAG–Fc (25 µg/ml). RhoA activity is indicated by the amount of RBD-bound RhoA normalized to the amount of RhoA in the lysates. Values represent RhoA activity relative to the cells at time 0. Results are means ± SE from three experiments. Asterisks indicate statistical significance (*p < 0.01, Student's t test). (B) NGF rapidly inhibits RhoA activity (10 min). (C) Dose response. (D) The activation was lost in the neurons from mice carrying a mutation in the p75NTR gene.

Colocalization of p75^NTR and MAG binding
MAG binds to neurons in a sialic acid–dependent manner, but MAG's sialic acid binding site is distinct from its neurite inhibitory activity. The sialic acid–dependent binding to MAG is not sufficient or necessary for MAG's inhibitory effect (Tang et al., 1997a). Therefore, it is possible that the binding partner and the signal transducing element for MAG may form a receptor complex. We assumed that the binding partner for MAG and p75^NTR might interact in a cis manner. To test this hypothesis, the localization of p75^NTR and MAG binding was assessed on the subcellular level. Binding of MAG–Fc was visualized by incubation with a fluorescent-tagged anti–human IgG. Fig. 4 shows binding of MAG–Fc to adult DRG neurons using confocal laser microscopy. MAG–Fc binding appears punctate. The same cells were stained with an anti-p75^NTR antibody, and the distribution was assessed. p75^NTR expression on the cell body was rather diffuse but that on the neurites showed fine speckled staining (Fig. 4 A, top). The vast majority of puncta for p75^NTR immunoreactivity was colocalized with MAG binding. At high magnification, the colocalization was evident by the similar distribution of hot spots on the neuritic plasma membrane (Fig. 4 A, bottom). Binding of MAG–Fc was still observed in DRG neurons from mice carrying a mutation in the p75^NTR gene (Fig. 4 B). These data demonstrate that the p75^NTR and MAG binding colocalize.

View larger version (22K): [in this window] [in a new window]   Figure 4. Colocalization of p75NTR and MAG binding. (A) DRG neurons were stained with the anti-p75NTR antibody and an Alexa fluorTM 568–conjugated secondary antibody. Binding of MAG–Fc was visualized by incubation with the FITC-tagged anti–human IgG. Confocal microscopy was performed on a ZEISS LSM-510 laser scanning microscope. Representative single optical sections for p75NTR (left), MAG binding (middle), and overlay images (right) are shown. Close association of these markers on the neurites was seen in almost all of the neurons with p75NTR immunoreactivity. (B) Binding of MAG–Fc to DRG neurons from mice carrying a mutation in the p75NTR gene.

View larger version (40K): [in this window] [in a new window]   Figure 5. Association of MAG, p75NTR, and GT1b. (A) Coprecipitation of p75NTR and MAG–Fc using lysates prepared from P9 cerebellum. In the MAG–Fc precipitates, the anti-p75NTR antibody revealed the presence of a protein corresponding to p75NTR. (B) Coprecipitation of recombinant p75NTR and GT1b. Association was examined by Western blot analysis of the precipitates produced with protein A sepharose and Fc-fused protein of p75NTR. The anti-GT1b antibody revealed the presence of a 100-kD protein (left), which was shown to be p75NTR by the anti-p75NTR antibody (right). (C) Coprecipitation of recombinant p75NTR and other gangliosides. (D) Coimmunoprecipitation of p75NTR and GT1b using lysates prepared from P9 cerebellum. In the GT1b immunoprecipitates, the anti-p75NTR antibody revealed the presence of a protein corresponding to p75NTR. The bottom bands correspond to the Ig of the antibodies used. (E) Coimmunoprecipitation of p75NTR and GT1b using transfected 293 cells. In the p75NTR immunoprecipitates, the anti-GT1b antibody revealed the presence of a protein (left), which was shown to be p75NTR by the anti-p75NTR antibody (right).

Dual signals elicited by p75^NTR
p75^NTR has been shown to bind more than just neurotrophins, such as CRNF (Fainzilber et al., 1996) or rabies virus glycoprotein (Tuffereau et al., 1998), but it is not known if these ligands trigger any signals through p75^NTR. Thus, our findings demonstrating that p75^NTR is a signal transducer not only for neurotrophins but also for MAG is intriguing. More interestingly, neurotrophins binding to p75^NTR promote axonal outgrowth of neurons presumably by inhibiting RhoA activity (Yamashita et al., 1999), but MAG elicits the opposite effect via p75^NTR on neurons by activating RhoA. This implies that p75^NTR has dual signals as a transducing element. It is also important to note that essentially all adult neurons are sensitive to inhibition by MAG, whereas p75^NTR has a restricted distribution. The identification and characterization of MAG signals have shed light on a previously unrecognized mechanism by which neurons respond to extracellular inhibitory molecules.

	Materials and methods

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Animals
The strain of mice bearing a targeted disruption of the third exon of the p75^NTR gene (Lee et al., 1992) that was originally obtained from Jackson ImmunoResearch Laboratories on a C57BL/6J background was used.

Neurite outgrowth assay
DRGs were removed from adult mice and dissociated into single cells by incubation with 0.025% trypsin and 0.15% collagenase type I (Sigma-Aldrich) for 30 min at 37°C. For cerebellar neurons, the cerebella from two animals were combined in 5 ml of 0.025% trypsin, triturated, and incubated for 10 min at 37°C. DME containing 10% FCS was added, and the cells were centrifuged at 800 rpm. Neurons were plated in Sato medium (Cai et al., 1999) on poly-L-lysine–coated chamber slides. For outgrowth assays, plated cells were incubated for 24 h, fixed in 4% (wt/vol) paraformaldehyde, and immunostained with a monoclonal antibody (TuJ1) recognizing the neuron-specific ß–tubulin III protein. Then, the length of the longest neurite or the total process outgrowth for each ß–tubulin III–positive neuron was determined. Where indicated, recombinant rat MAG–Fc chimera (R&D Systems) was added to the medium after plating. The recombinant C3 transferase was introduced into the cytoplasm of the neurons before plating by trituration as described previously (Borasio et al., 1989).

Affinity precipitation of GTP–RhoA
293 cells were transfected with pcDNA3 vectors containing wild-type NH₂-terminally HA-tagged RhoA (Yamashita et al., 1999) and/or full-length human p75^NTR by lipofection using Lipofectamine 2000 (GIBCO BRL). Cerebellar neurons from P9 mice were isolated as described previously (Cai et al., 1999). Cells were lysed in 50 mM Tris, pH 7.5, 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, 500 mM NaCl, and 10 mM MgCl₂ with leupeptin and aprotinin each at 10 µg/ml. Cell lysates were clarified by centrifugation at 13,000 g at 4°C for 10 min, and the supernatants were incubated with the 20 µg of GST-Rho binding domain of Rhotekin beads (Upstate Biotechnology) at 4°C for 45 min. The beads were washed four times with washing buffer (50 mM Tris, pH 7.5, containing 1% Triton X-100, 150 mM NaCl, 10 mM MgCl₂,10 µg/ml each of leupeptin and aprotinin). Bound Rho proteins were detected by Western blotting using a monoclonal antibody against RhoA (Santa Cruz Biotechnology).

MAG–Fc binding and immunocytochemistry
DRG neuron cultures were fixed in 1% paraformaldehyde in PBS for 30 min. They were then blocked in PBS containing 2% FCS. To localize the MAG binding molecule, MAG–Fc (5 µg/ml) and anti–human IgG (1µg/ml) were precomplexed for 30 min at room temperature before being added to the fixed and blocked DRG neurons (Turnley and Bartlett, 1999). To identify p75^NTR, cells were permeabilized with 0.2% Triton X-100/PBS and then incubated overnight with polyclonal antibody to p75^NTR (Promega) followed by an Alexa fluor^TM 568–labeled anti–rabbit IgG (Molecular Probes) for 1 h. The specificity of the antibodies was assessed by Western blot analysis of cells expressing the proteins, and control experiments of immunocytochemistry were performed by leaving out the primary antibodies.

Coprecipitation of recombinant p75^NTR and GT1b
Recombinant human p75–Fc chimera (1 µg; Genzyme-Techne) and 1 µg of purified ganglioside GT1b (>98% purity; Seikagaku Co.) were incubated in 200 µl 0.025% Tween 20/PBS for 2 h, and p75^NTR was precipitated using protein A sepharose (Amersham Pharmacia Biotech). The resultant precipitates were electrophoretically transferred to polyvinylidene difluoride membranes after SDS-PAGE with 7% gels and were immunoblotted with anti-GT1b antibody (IgM; Seikagaku Co.) or anti-p75^NTR antibody.

Coimmunoprecipitation experiments
Cells were lysed on ice for 20 min with lysis buffer (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% Triton X-100, 25 µg/ml leupeptin, and 25 µg/ml aprotinin). The lysates were centrifuged at 13,000 g for 20 min, and the supernatants were collected. They were then incubated with the anti-GT1b antibody or an anti-HA antibody (for transfected HA-p75^NTR) overnight followed by incubation with the anti–mouse IgM antibody (for GT1b). Immunocomplex or MAG–Fc was collected with protein A sepharose (Amersham Pharmacia Biotech). The suspension was centrifuged at 1,000 g for 5 min. The pellets were washed four times with lysis buffer and subjected to SDS-PAGE followed by immunoblot analysis.

	Footnotes

 
^* Abbreviations used in this paper: DRG, dorsal root ganglion; MAG, myelin-associated glycoprotein; p75^NTR, the neurotrophin receptor p75.

	Acknowledgments

 
This work was supported by a Grant-in-Aid from Senri Life Science Foundation.

Submitted: 4 February 2002

Revised: 29 March 2002

Accepted: 29 March 2002

	References

Top Abstract Introduction Results and discussion Materials and methods References

 

Borasio, G.D., J. John, A. Wittinghofer, Y.A. Barde, M. Sendtner, and R. Heumann. 1989. ras p21 protein promotes survival and fiber outgrowth of cultured embryonic neurons. Neuron. 2:1087–1096.[CrossRef][Medline]

Buck, C.R., H.J. Martinez, I.B. Black, and M.V. Chao. 1987. Developmentally regulated expression of the nerve growth factor receptor gene in the periphery and brain. Proc. Natl. Acad. Sci. USA. 84:3060–3063.[Abstract/Free Full Text]

Cai, D., Y. Shen, M. De Bellard, S. Tang, and M.T. Filbin. 1999. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron. 22:89–101.[CrossRef][Medline]

Davies, A.M. 2000. Neurotrophins: neurotrophic modulation of neurite growth. Curr. Biol. 10:R198–R200.[CrossRef][Medline]

Ernfors, P., F. Hallbook, T. Ebendal, E.M. Shooter, M.J. Radeke, T.P. Misko, and H. Persson. 1988. Developmental and regional expression of beta-nerve growth factor receptor mRNA in the chick and rat. Neuron. 1:983–996.[CrossRef][Medline]

Ernfors, P., A. Henschen, L. Olson, and H. Persson. 1989. Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron. 2:1605–1613.[CrossRef][Medline]

Fainzilber, M., A.B. Smit, N.I. Syed, W.C. Wildering, P..M. Hermann, R.C. van der Schors, C. Jimenez, K.W. Li, J. van Minnen, A.G. Bulloch, C.F. Ibanez, and W.P. Geraerts. 1996. CRNF, a molluscan neurotrophic factor that interacts with the p75 neurotrophin receptor. Science. 274:1540–1543.[Abstract/Free Full Text]

Kimpinski, K., K.S. Jelinski, and K. Mearow. 1999. The anti-p75 antibody, MC192, and brain-derived neurotrophic factor inhibit nerve growth factor-dependent neurite growth from adult sensory neurons. Neuroscience. 93:253–263.[CrossRef][Medline]

Kohn, J., R.S. Aloyz, J.G. Toma, M. Haak-Frendscho, and F.D. Miller. 1999. Functionally antagonistic interactions between the TrkA and p75 neurotrophin receptors regulate sympathetic neuron growth and target innervation. J. Neurosci. 19:5393–5408.[Abstract/Free Full Text]

Large, T.H., G. Weskamp, J.C. Helder, M.J. Radeke, T.P. Misko, E.M. Shooter, and L.F. Reichardt. 1989. Structure and developmental expression of the nerve growth factor receptor in the chicken central nervous system. Neuron. 2:1123–1134.[CrossRef][Medline]

Lee, K.F., E. Li, L.J. Huber, S.C. Landis, A.H. Sharpe, M.V. Chao, and R. Jaenisch. 1992. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell. 69:737–749.[CrossRef][Medline]

Lehmann, M., A. Fournier, I. Selles-Navarro, P. Dergham, A. Sebok, N. Leclerc, G. Tigyi, and L. McKerracher. 1999. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19:7537–7547.[Abstract/Free Full Text]

McKerracher, L., S. David, D.L. Jackson, V. Kottis, R.J. Dunn, and P.E. Braun. 1994. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron. 13:805–811.[CrossRef][Medline]

Mukhopadhyay, G., P. Doherty, F.S. Walsh, P.R. Crocker, and M.T. Filbin. 1994. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron. 13:757–767.[CrossRef][Medline]

Ren, X.D., W.B. Kiosses, and M.A. Schwartz. 1999. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskelton. EMBO J. 18:578–585.[CrossRef][Medline]

Roux, P.P., M.A. Colicos, P.A. Barker, and T.E. Kennedy. 1999. p75 neurotrophin receptor expression is induced in apoptotic neurons after seizure. J. Neurosci. 19:6887–6896.[Abstract/Free Full Text]

Sheikh, K.A., J. Sun, Y. Liu, H. Kawai, T.O. Crawford, R.L. Proia, J.W. Griffin, and R.L. Schnaar. 1999. Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc. Natl. Acad. Sci. USA. 96:7532–7537.[Abstract/Free Full Text]

Tang, S., Y.J. Shen, M.E. DeBellard, G. Mukhopadhyay, J.L. Salzer, P.R. Crocker, and M.T. Filbin. 1997a. Myelin-associated glycoprotein interacts with neurons via a sialic acid binding site at ARG118 and a distinct neurite inhibition site. J. Cell Biol. 138:1355–1366.[Abstract/Free Full Text]

Tang, S., R.W. Woodhall, Y.J. Shen, M.E. deBellard, J.L. Saffell, P. Doherty, F.S. Walsh, and M.T. Filbin. 1997b. Soluble myelin-associated glycoprotein found in vivo inhibits axonal regeneration. Mol. Cell. Neurosci. 9:333–346.[CrossRef][Medline]

Tuffereau, C., J. Benejean, D. Blondel, B. Kieffer, and A. Flamand. 1998. Low-affinity nerve-growth factor receptor (P75NTR) can serve as a receptor for rabies virus. EMBO J. 17:7250–7259.[CrossRef][Medline]

Turnley, A.M., and P.F. Bartlett. 1999. Nerve growth factor modulates myelin-associated glycoprotein binding to sensory neurons. Int. J. Dev. Neurosci. 17:109–119.[CrossRef][Medline]

Vinson, M., P.J. Strijbos, A. Rowles, L. Facci, S.E. Moore, D.L. Simmons, and F.S. Walsh. 2001. Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition. J. Biol. Chem. 276:20280–20285.[Abstract/Free Full Text]

von Bartheld, C.S., J.G. Heuer, and M. Bothwell. 1991. Expression of nerve growth factor (NGF) receptors in the brain and retina of chick embryos: comparison with cholinergic development. J. Comp. Neurol. 310:103–129.[CrossRef][Medline]

Walsh, G.S., K.M. Krol, K.A. Crutcher, and M.D. Kawaja. 1999. Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. J. Neurosci. 19:4155–4168.[Abstract/Free Full Text]

Yamashita, T., K.L. Tucker, and Y.A. Barde. 1999. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron. 24:585–593.[CrossRef][Medline]

Yan, Q., and E.M. Johnson, Jr. 1988. An immunohistochemical study of the nerve growth factor receptor in developing rats. J. Neurosci. 8:3481–3498.[Abstract]

Yang, L.J., C.B. Zeller, N.L. Shaper, M. Kiso, A. Hasegawa, R.E. Shapiro, and R.L. Schnaar. 1996. Gangliosides are neuronal ligands for myelin-associated glycoprotein. Proc. Natl. Acad. Sci. USA. 93:814–818.[Abstract/Free Full Text]

Yeo, T.T., J. Chua-Couzens, L.L. Butcher, D.E. Bredesen, J.D. Cooper, J.S. Valletta, W.C. Mobley, and F.M. Longo. 1997. Absence of p75NTR causes increased basal forebrain cholinergic neuron size, choline acetyltransferase activity, and target innervation. J. Neurosci. 17:7594–7605.[Abstract/Free Full Text]

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• Venkatesh, K., Chivatakarn, O., Sheu, S.-S., Giger, R. J. (2007). Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type-specific mechanisms for neurite outgrowth inhibition. J. Cell Biol. 177: 393-399 [Abstract] [Full Text]  
• Arevalo, M.-A., Rodriguez-Tebar, A. (2006). Activation of Casein Kinase II and Inhibition of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Phosphatase by Nerve Growth Factor/p75NTR Inhibit Glycogen Synthase Kinase-3beta and Stimulate Axonal Growth. Mol. Biol. Cell 17: 3369-3377 [Abstract] [Full Text]  
• Zhou, F.-Q., Walzer, M., Wu, Y.-H., Zhou, J., Dedhar, S., Snider, W. D. (2006). Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism. J. Cell Sci. 119: 2787-2796 [Abstract] [Full Text]  
• Mimura, F., Yamagishi, S., Arimura, N., Fujitani, M., Kubo, T., Kaibuchi, K., Yamashita, T. (2006). Myelin-associated Glycoprotein Inhibits Microtubule Assembly by a Rho-kinase-dependent Mechanism. J. Biol. Chem. 281: 15970-15979 [Abstract] [Full Text]  
• Ahmed, Z., Suggate, E. L., Brown, E. R., Dent, R. G., Armstrong, S. J., Barrett, L. B., Berry, M., Logan, A. (2006). Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro. Brain 129: 1517-1533 [Abstract] [Full Text]  
• Logan, A., Ahmed, Z., Baird, A., Gonzalez, A. M., Berry, M. (2006). Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain 129: 490-502 [Abstract] [Full Text]  
• Varki, A., Angata, T. (2006). Siglecs--the major subfamily of I-type lectins. Glycobiology 16: 1R-27R [Abstract] [Full Text]  
• Zagrebelsky, M., Holz, A., Dechant, G., Barde, Y.-A., Bonhoeffer, T., Korte, M. (2005). The p75 Neurotrophin Receptor Negatively Modulates Dendrite Complexity and Spine Density in Hippocampal Neurons. J. Neurosci. 25: 9989-9999 [Abstract] [Full Text]  
• SKAPER, S. D. (2005). Neuronal Growth-Promoting and Inhibitory Cues in Neuroprotection and Neuroregeneration. Ann. N. Y. Acad. Sci. 1053: 376-385 [Abstract] [Full Text]  
• Vyas, A. A., Blixt, O., Paulson, J. C., Schnaar, R. L. (2005). Potent Glycan Inhibitors of Myelin-associated Glycoprotein Enhance Axon Outgrowth in Vitro. J. Biol. Chem. 280: 16305-16310 [Abstract] [Full Text]  
• Yamashita, T., Wu, Y.-P., Sandhoff, R., Werth, N., Mizukami, H., Ellis, J. M., Dupree, J. L., Geyer, R., Sandhoff, K., Proia, R. L. (2005). Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions. Proc. Natl. Acad. Sci. USA 102: 2725-2730 [Abstract] [Full Text]  
• Venkatesh, K., Chivatakarn, O., Lee, H., Joshi, P. S., Kantor, D. B., Newman, B. A., Mage, R., Rader, C., Giger, R. J. (2005). The Nogo-66 Receptor Homolog NgR2 Is a Sialic Acid-Dependent Receptor Selective for Myelin-Associated Glycoprotein. J. Neurosci. 25: 808-822 [Abstract] [Full Text]  
• Govek, E.-E., Newey, S. E., Van Aelst, L. (2005). The role of the Rho GTPases in neuronal development. Genes Dev. 19: 1-49 [Abstract] [Full Text]  
• Salama-Cohen, P., Arevalo, M.-A., Meier, J., Grantyn, R., Rodriguez-Tebar, A. (2005). NGF Controls Dendrite Development in Hippocampal Neurons by Binding to p75NTR and Modulating the Cellular Targets of Notch. Mol. Biol. Cell 16: 339-347 [Abstract] [Full Text]  
• Ramer, L. M., Borisoff, J. F., Ramer, M. S. (2004). Rho-Kinase Inhibition Enhances Axonal Plasticity and Attenuates Cold Hyperalgesia after Dorsal Rhizotomy. J. Neurosci. 24: 10796-10805 [Abstract] [Full Text]  
• Hartmann, M., Brigadski, T., Erdmann, K. S., Holtmann, B., Sendtner, M., Narz, F., Lessmann, V. (2004). Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor. J. Cell Sci. 117: 5803-5814 [Abstract] [Full Text]  
• Goldshmit, Y., Galea, M. P., Wise, G., Bartlett, P. F., Turnley, A. M. (2004). Axonal Regeneration and Lack of Astrocytic Gliosis in EphA4-Deficient Mice. J. Neurosci. 24: 10064-10073 [Abstract] [Full Text]  
• Li, W., Walus, L., Rabacchi, S. A., Jirik, A., Chang, E., Schauer, J., Zheng, B. H., Benedetti, N. J., Liu, B. P., Choi, E., Worley, D., Silvian, L., Mo, W., Mullen, C., Yang, W., Strittmatter, S. M., Sah, D. W. Y., Pepinsky, B., Lee, D. H. S. (2004). A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin. J. Biol. Chem. 279: 43780-43788 [Abstract] [Full Text]  
• Sun, J., Shaper, N. L., Itonori, S., Heffer-Lauc, M., Sheikh, K. A., Schnaar, R. L. (2004). Myelin-associated glycoprotein (Siglec-4) expression is progressively and selectively decreased in the brains of mice lacking complex gangliosides. Glycobiology 14: 851-857 [Abstract] [Full Text]  
• Hasegawa, Y., Fujitani, M., Hata, K., Tohyama, M., Yamagishi, S., Yamashita, T. (2004). Promotion of Axon Regeneration by Myelin-Associated Glycoprotein and Nogo through Divergent Signals Downstream of Gi/G. J. Neurosci. 24: 6826-6832 [Abstract] [Full Text]  
• Bandtlow, C., Dechant, G. (2004). From Cell Death to Neuronal Regeneration, Effects of the p75 Neurotrophin Receptor Depend on Interactions with Partner Subunits. Sci Signal 2004: pe24-pe24 [Abstract] [Full Text]  
• KIRYUSHKO, D., BEREZIN, V., BOCK, E. (2004). Regulators of Neurite Outgrowth: Role of Cell Adhesion Molecules. Ann. N. Y. Acad. Sci. 1014: 140-154 [Abstract] [Full Text]  
• Garcia, M. L., Lobsiger, C. S., Shah, S. B., Deerinck, T. J., Crum, J., Young, D., Ward, C. M., Crawford, T. O., Gotow, T., Uchiyama, Y., Ellisman, M. H., Calcutt, N. A., Cleveland, D. W. (2003). NF-M is an essential target for the myelin-directed "outside-in" signaling cascade that mediates radial axonal growth. J. Cell Biol. 163: 1011-1020 [Abstract] [Full Text]  
• Blixt, O., Collins, B. E., van den Nieuwenhof, I. M., Crocker, P. R., Paulson, J. C. (2003). Sialoside Specificity of the Siglec Family Assessed Using Novel Multivalent Probes: IDENTIFICATION OF POTENT INHIBITORS OF MYELIN-ASSOCIATED GLYCOPROTEIN. J. Biol. Chem. 278: 31007-31019 [Abstract] [Full Text]  
• Dubreuil, C. I., Winton, M. J., McKerracher, L. (2003). Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J. Cell Biol. 162: 233-243 [Abstract] [Full Text]  
• Oertle, T., van der Haar, M. E., Bandtlow, C. E., Robeva, A., Burfeind, P., Buss, A., Huber, A. B., Simonen, M., Schnell, L., Brosamle, C., Kaupmann, K., Vallon, R., Schwab, M. E. (2003). Nogo-A Inhibits Neurite Outgrowth and Cell Spreading with Three Discrete Regions. J. Neurosci. 23: 5393-5406 [Abstract] [Full Text]  
• Kanning, K. C., Hudson, M., Amieux, P. S., Wiley, J. C., Bothwell, M., Schecterson, L. C. (2003). Proteolytic Processing of the p75 Neurotrophin Receptor and Two Homologs Generates C-Terminal Fragments with Signaling Capability. J. Neurosci. 23: 5425-5436 [Abstract] [Full Text]  
• Niederost, B., Oertle, T., Fritsche, J., McKinney, R. A., Bandtlow, C. E. (2002). Nogo-A and Myelin-Associated Glycoprotein Mediate Neurite Growth Inhibition by Antagonistic Regulation of RhoA and Rac1. J. Neurosci. 22: 10368-10376 [Abstract] [Full Text]  
• Kubo, T., Yamashita, T., Yamaguchi, A., Sumimoto, H., Hosokawa, K., Tohyama, M. (2002). A Novel FERM Domain Including Guanine Nucleotide Exchange Factor Is Involved in Rac Signaling and Regulates Neurite Remodeling. J. Neurosci. 22: 8504-8513 [Abstract] [Full Text]  
• Tanaka, H., Yamashita, T., Asada, M., Mizutani, S., Yoshikawa, H., Tohyama, M. (2002). Cytoplasmic p21Cip1/WAF1 regulates neurite remodeling by inhibiting Rho-kinase activity. J. Cell Biol. 158: 321-329 [Abstract] [Full Text]  
• Kwon, B. K., Borisoff, J. F., Tetzlaff, W. (2002). Molecular Targets for Therapeutic Intervention after Spinal Cord Injury. Mol. Interv. 2: 244-258 [Abstract] [Full Text]  
• McKerracher, L. (2002). Ganglioside rafts as MAG receptors that mediate blockade of axon growth. Proc. Natl. Acad. Sci. USA 99: 7811-7813 [Full Text]  

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