A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin

Li, Weiwei; Walus, Lee; Rabacchi, Sylvia A.; Jirik, Adrienna; Chang, Ernie; Schauer, Jessica; Zheng, Betty; Benedetti, Nancy J.; Liu, Betty P.; Choi, Eugene; Worley, Dane; Silvian, Laura; Mo, Wenjun; Mullen, Colleen; Yang, Wenzhong; Strittmatter, Stephen M.; Sah, Dinah W.Y.; Pepinsky, Blake; Lee, Daniel H. S.

doi:10.1074/jbc.m401803200

Cited by 59 publications

(47 citation statements)

References 34 publications

(45 reference statements)

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“…In addition, the Nogo receptor LRR domain has been implicated in trans interactions. Similar to our data indicating that an antibody to the SALM LRR domain inhibits SALM4 trans-cellular associations, a monoclonal antibody to the third LRR of Nogo receptor reverses the inhibition of neurite outgrowth by myelin and blocks binding of the Nogo receptor ligands Nogo, myelinassociated glycoprotein, and oligodendrocyte-myelin glycoprotein (59).…”

Section: Discussionsupporting

confidence: 90%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1-3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites.Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1-4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5-7). The importance of these molecules is illustrated in cases of dysfunctional adhesion molecules that have been associated with specific disorders in humans, including SLITRK1 in Tourette syndrome (8) and neuroligin in autism (9, 10). Whereas our understanding of the role of adhesion molecules in neuronal development is rapidly increasing, little is known about their functions, and it is likely that many remain to be identified.Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11-13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11-13). SALMs are expressed early in the developing nervous system and persist into adulthood. They are present at the synaptic membrane as well as at non-synaptic locations. SALM1 overe...

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Section: Discussionsupporting

confidence: 90%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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“…In part, cell-intrinsic programs limit axonal regeneration (Liu et al, 2011). In addition, the adult CNS is an inhibitory environment due to the expression of chondroitin sulfate proteoglycans (Yiu and He, 2006) and myelin-associated inhibitors (NogoA, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein; Akbik et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…These molecules restrict axon growth by signaling through neuron-specific Nogo Receptors 1 and 3 (NgR1, (Fournier et al, 2001;Dickendesher et al, 2012), PirB (Atwal et al, 2008), PTPsigma (Shen et al, 2009;Fry et al, 2010), leukocyte common antigen-related phosphatase (Fisher et al, 2011), and the sphingolipid receptor S1PR2 (Kempf et al, 2014). Receptor antagonism via either genetic perturbation Simonen et al, 2003;Kim et al, 2004;Dimou et al, 2006;Cafferty et al, 2010;Dickendesher et al, 2012;Bartus et al, 2014) or pharmacological treatment (Schnell and Schwab, 1990;Bradbury et al, 2002;GrandPré et al, 2002;Liebscher et al, 2005;Wang et al, 2006;Wang et al, 2011;Lang et al, 2015) results in enhanced (yet incomplete) recovery of motor function after experimental SCI (Basso et al, 1995;Basso et al, 2006). In general, the anatomical substrate supporting functional recovery remains unclear and correlative.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to universally adopted SCI behavioral assessments such as BMS and BBB, methods to label motor tracts such as the corticospinal tract (CST) vary widely (Steward et al, 2008b;. Therefore, important anatomical data can be lost, overinterpreted, and difficult to reproduce Simonen et al, 2003;Woolf, 2003;Zheng et al, 2005;Cafferty et al, 2007a;Steward et al, 2007;Steward et al, 2008a;Steward et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive Corticospinal Labeling withmu-crystallinTransgene Reveals Axon Regeneration after Spinal Cord Trauma inngr1^−/−Mice

Fink

Strittmatter

Cafferty³

2015

J. Neurosci.

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Spinal cord injury interrupts descending motor tracts and creates persistent functional deficits due to the absence of spontaneous axon regeneration. Of descending pathways, the corticospinal tract (CST) is thought to be the most critical for voluntary function in primates. Even with multiple tracer injections and genetic tools, the CST is visualized to only a minor degree in experimental studies. Here, we identify and validate the mu-crystallin (crym) gene as a high-fidelity marker of the CST. In transgenic mice expressing green fluorescent protein (GFP) under crym regulatory elements (crym-GFP), comprehensive and near complete CST labeling is achieved throughout the spinal cord. Bilateral pyramidotomy eliminated the 17,000 GFP-positive CST axons that were reproducibly labeled in brainstem from the spinal cord. We show that CST tracing with crym-GFP is 10-fold more efficient than tracing with biotinylated dextran amine (BDA). Using crym-GFP, we reevaluated the CST in mice lacking nogo receptor 1 (NgR1), a protein implicated in limiting neural repair. The number and trajectory of CST axons in ngr1 Ϫ / Ϫ mice without injury was indistinguishable from ngr1 ϩ/ϩ mice. After dorsal hemisection in the midthoracic cord, CST axons did not significantly regenerate in ngr1 ϩ/ϩ mice, but an average of 162 of the 6000 labeled thoracic CST axons (2.68%) regenerated Ͼ100 m past the lesion site in crym-GFP ngr1 Ϫ / Ϫ mice. Although traditional BDA tracing cannot reliably visualize regenerating ngr1 Ϫ / Ϫ CST axons, their regenerative course is clear with crym-GFP. Therefore the crym-GFP transgenic mouse is a useful tool for studies of CST anatomy in experimental studies of motor pathways.

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“…The discovery of an anti-NgR monoclonal antibody, capable of inhibiting binding of Nogo, MAG, and OMgp, and of blocking inhibition of myelin in vitro, has now been reported. 54 Downstream of NgR are several other molecules that might also serve as targets for intervention after SCI. The Nogo receptor is thought to transmit myelininhibitory signaling through its interaction with the low-affinity neurotrophin receptor p75.…”

Section: Myelin and Myelin Signaling: An Inhibitory Chorus Linementioning

confidence: 99%

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

2005

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Here we review mechanisms and molecules that necessitate protection and oppose axonal growth in the injured spinal cord, representing not only a cast of villains but also a company of therapeutic targets, many of which have yet to be fully exploited. We next discuss recent progress in the fields of bridging, overcoming conduction block and rehabilitation after spinal cord injury (SCI), where several treatments in each category have entered the spotlight, and some are being tested clinically. Finally, studies that combine treatments targeting different aspects of SCI are reviewed. Although experiments applying some treatments in combination have been completed, auditions for each part in the much-sought combination therapy are ongoing, and performers must demonstrate robust anatomical regeneration and/or significant return of function in animal models before being considered for a lead role.Spinal Cord (2005) 43, 134-161.

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A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin

Cited by 59 publications

References 34 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Comprehensive Corticospinal Labeling withmu-crystallinTransgene Reveals Axon Regeneration after Spinal Cord Trauma inngr1^−/−Mice

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

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A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin

Cited by 59 publications

References 34 publications

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Comprehensive Corticospinal Labeling withmu-crystallinTransgene Reveals Axon Regeneration after Spinal Cord Trauma inngr1−/−Mice

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

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Product

Resources

About

Comprehensive Corticospinal Labeling withmu-crystallinTransgene Reveals Axon Regeneration after Spinal Cord Trauma inngr1^−/−Mice