Truncated Soluble Nogo Receptor Binds Nogo-66 and Blocks Inhibition of Axon Growth by Myelin

Fournier, Alyson E.; Gould, Graham C.; Liu, Betty P.; Strittmatter, Stephen M.

doi:10.1523/jneurosci.22-20-08876.2002

Cited by 196 publications

(178 citation statements)

References 31 publications

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“…A change in conformation might explain why SALM2 does not form transcellular interactions under normal conditions, but treatment of epitope-tagged SALM2 transfected cells with a Myc antibody induces clustering of the SALM2 C terminus at cell junctions. A similar change in ectodomain conformation has been suggested for the Nogo receptor, a LRR containing receptor involved in the inhibition of neurite outgrowth (56,57). The crystal structure of the Nogo receptor ectodomain (56,58), as well as binding assays (57), suggest that the LRR can form multimers.…”

Section: Discussionsupporting

confidence: 56%

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: 56%

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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“…The success of the former approach will depend on whether the binding sites for the three inhibitors on Ngr are distinct or overlapping. The ligand binding region for all three inhibitors has already been shown to require the first eight LRRs of Ngr, but not the LLRCT region 45,71 , whereas both of these regions are needed for interaction with p75 NTR and inhibition 38 . Recently, a 40-amino-acid peptide corresponding to a…”

Section: Overcoming Inhibitors Of Regeneration In Myelinmentioning

confidence: 98%

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

2003

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“…To test whether the GFAP-positive cells express and secrete NgR(310)ecto protein in heterozygous-transgenic mice, homogenates of cerebral cortex and spinal cord were examined by Western blot analysis using antibody raised against NgR. This antibody detects an ~80-kDa protein species in homogenates of cortex and spinal cord as in the NgR-transfected HEK293T cells (Domeniconi et al, 2002;Fournier et al, 2002). As expected, the secreted 37-kDa NgR(310)ecto protein is detected in detergent-free soluble extracts of cortex and spinal cord from the two transgenic lines Tg08 and Tg01 without injury (Fig.…”

Section: Transgenic Expression Of Ngr(310)ectomentioning

confidence: 99%

“…The LRR cassette is connected at its carboxyl end via a 100 aa stalk to a GPI anchorage site on the exterior of the plasma membrane. Nogo-66, MAG, and OMgp bind exclusively to the LRRNT/LRR/LRRCT region (Barton et al, 2003;Fournier et al, 2002;He et al, 2003;Liu et al, 2002). The 100 aa carboxyl linker region is required for signaling but not for ligand binding .…”

Section: Introductionmentioning

confidence: 99%

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Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury

Kim

Budel

et al. 2005

Molecular and Cellular Neuroscience

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100

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Axon growth after spinal injury is thought to be limited in part by myelin-derived proteins that act via the Nogo-66 Receptor (NgR). To test this hypothesis, we sought to study recovery from spinal cord injury (SCI) after inhibiting NgR transgenically with a soluble function-blocking NgR fragment. Glial fibrillary acidic protein (gfap) gene regulatory elements were used to generate mice that secrete NgR(310)ecto from astrocytes. After mid-thoracic dorsal over-hemisection injury, gfap∷ngr(310)ecto mice exhibit enhanced raphespinal and corticospinal axonal sprouting into the lumbar spinal cord. Recovery of locomotion is improved in the gfap∷ngr(310)ecto mice. These data indicate that the NgR ligands, Nogo-66, MAG, and OMgp, play a role in limiting axonal growth in the injured adult CNS and that NgR(310)ecto might provide a therapeutic means to promote recovery from SCI.

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Truncated Soluble Nogo Receptor Binds Nogo-66 and Blocks Inhibition of Axon Growth by Myelin

Cited by 196 publications

References 31 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

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury

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