Reticulon 4

RTN4
Identifiers
Aliases	RTN4, ASY, NI220/250, NOGO, NOGO-A, NOGOC, NSP, NSP-CL, Nbla00271, Nbla10545, Nogo-B, Nogo-C, RTN-X, RTN4-A, RTN4-B1, RTN4-B2, RTN4-C, Reticulon 4
External IDs	OMIM: 604475; MGI: 1915835; GeneCards: RTN4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2G31, 2JV5
Gene location (Human)
Chr.	Chromosome 2 (human)
End	55,112,621 bp
Gene location (Mouse)
Chr.	Chromosome 11 (mouse)
End	29,694,331 bp
RNA expression pattern
	Top expressed in
	pons; ; parietal lobe; ; postcentral gyrus; ; superior vestibular nucleus; ; subthalamic nucleus; ; lateral nuclear group of thalamus; ; orbitofrontal cortex; ; pars compacta; ; pars reticulata; ; inferior ganglion of vagus nerve;
	Top expressed in
	dorsal striatum; ; pontine nuclei; ; habenula; ; cingulate gyrus; ; lateral geniculate nucleus; ; deep cerebellar nuclei; ; medial dorsal nucleus; ; endothelial cell of lymphatic vessel; ; Epithelium of choroid plexus; ; olfactory tubercle;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	protein binding; RNA binding; cadherin binding; ubiquitin protein ligase binding;
Cellular component	integral component of membrane; cell projection; nuclear envelope; membrane; integral component of endoplasmic reticulum membrane; intracellular anatomical structure; endoplasmic reticulum; endoplasmic reticulum membrane; plasma membrane; extracellular exosome; postsynaptic density; endoplasmic reticulum tubular network; soma; endoplasmic reticulum tubular network membrane; cell junction;
Biological process	nuclear pore complex assembly; regulation of apoptotic process; cerebral cortex radial glia-guided migration; regulation of branching morphogenesis of a nerve; cardiac epithelial to mesenchymal transition; negative regulation of axon extension; apoptotic process; negative regulation of axonogenesis; nervous system development; regulation of nervous system development; endoplasmic reticulum tubular network formation; endoplasmic reticulum tubular network organization; regulation of cell migration; negative regulation of cell growth; axonal fasciculation; positive regulation of epithelial cell migration; positive regulation of mammary gland epithelial cell proliferation; protein stabilization; positive regulation of protein kinase B signaling; positive regulation of protein localization to endoplasmic reticulum; positive regulation of ERBB3 signaling pathway; endoplasmic reticulum tubular network membrane organization; blastocyst formation; positive regulation of toll-like receptor 9 signaling pathway; protein localization to lysosome; cellular sphingolipid homeostasis;
	Sources:Amigo / QuickGO
Orthologs
Databases	NCBI: entry; OMA: entry
	57142
	68585
	ENSG00000115310
	ENSMUSG00000020458
	Q9NQC3
	Q99P72
NM_007008; NM_020532; NM_153828; NM_207520; NM_207521;
	NM_001321859; NM_001321860; NM_001321861; NM_001321862; NM_001321863; NM_001321904
	NM_024226; NM_194051; NM_194052; NM_194053; NM_194054
NP_001308788; NP_001308789; NP_001308790; NP_001308791; NP_001308792;
	NP_001308833; NP_008939; NP_065393; NP_722550; NP_997403; NP_997404
	NP_077188; NP_918940; NP_918941; NP_918942; NP_918943
	Wikidata
View/Edit Human	View/Edit Mouse

Reticulon 4, also known as Neurite outgrowth inhibitor or Nogo, is a protein that in humans is encoded by the RTN4 gene. It belongs to the family of reticulon-encoding genes, whose members are associated with the endoplasmic reticulum and participate in neuroendocrine secretion and membrane trafficking in neuroendocrine cells. The product of this gene is a potent inhibitor of neurite outgrowth and is thought to contribute to the limited regenerative capacity of the central nervous system in higher vertebrates.

Structure

Alternatively spliced transcript variants derived from both differential splicing and differential promoter usage have been identified and encode distinct isoforms of Nogo. There are three known isoforms: Nogo-A, Nogo-B, and Nogo-C.

Nogo-A contains two characterized inhibitory domains: amino-Nogo at the N-terminus and Nogo-66, which forms the molecule's extracellular loop. Both domains participate in inhibitory signaling. Amino-Nogo acts as a strong inhibitor of neurite outgrowth, whereas Nogo-66 is involved in growth cone destruction.

Function

Nogo has been identified as an inhibitor of neurite outgrowth specific to the central nervous system.

During neural development, Nogo is expressed mainly by neurons and provides an inhibitory signal for the migration and sprouting of CNS endothelial (tip) cells, thereby restricting blood vessel density.

Nogo also has functions beyond axonal growth inhibition. It has been identified as a key mediator in the process through which physical exercise enhances learning and memory in the brain.

Nogo-A has additionally been shown to negatively regulate vascular growth and repair following ischemic stroke. Genetic deletion and antibody-mediated blockade of Nogo-A enhanced revascularization and functional recovery in an experimental mouse model of stroke.

Clinical significance

Because Nogo inhibits neurite regeneration, it has been investigated as a therapeutic target for nervous system repair. Research suggests that blocking Nogo-A following neuronal injury, including damage associated with diseases such as multiple sclerosis, may promote protection or restoration of injured neurons.

Investigation into the mechanisms of this protein has generated interest for the treatment of auto-immune mediated demyelinating diseases and spinal cord injury regeneration.

Following ischemic stroke, treatment with anti-Nogo-A antibodies was also found to reduce vascular leakage, a major complication associated with post-stroke tissue injury.

Interactions

Reticulon 4 has been shown to interact with WWP1, BCL2-like 1 and Bcl-2.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000115310 – Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020458 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
1 2 GrandPré T, Nakamura F, Vartanian T, Strittmatter SM (January 2000). "Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein". Nature. 403 (6768): 439–444. Bibcode:2000Natur.403..439G. doi:10.1038/35000226. PMID 10667797. S2CID 1926168.
1 2 Yang J, Yu L, Bi AD, Zhao SY (June 2000). "Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 88 (1–2): 101–102. doi:10.1159/000015499. PMID 10773680. S2CID 37521141.
1 2 3 "Entrez Gene: RTN4 reticulon 4".
1 2 Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, et al. (July 2004). "The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination". Nature Neuroscience. 7 (7): 736–744. doi:10.1038/nn1261. PMID 15184901. S2CID 9613584.
↑ Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, et al. (March 2008). "Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength". The Journal of Neuroscience. 28 (11): 2753–2765. doi:10.1523/JNEUROSCI.5586-07.2008. PMC 6670664. PMID 18337405.; Lay summary in: "Stopping a receptor called 'nogo' boosts the synapses". EurekAlert!.
↑ Rust R, Grönnert L, Gantner C, Enzler A, Mulders G, Weber RZ, et al. (July 2019). "Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke". Proceedings of the National Academy of Sciences of the United States of America. 116 (28): 14270–14279. Bibcode:2019PNAS..11614270R. doi:10.1073/pnas.1905309116. PMC 6628809. PMID 31235580.
↑ Rust R, Grönnert L, Weber RZ, Mulders G, Schwab ME (September 2019). "Refueling the Ischemic CNS: Guidance Molecules for Vascular Repair". Trends in Neurosciences. 42 (9): 644–656. doi:10.1016/j.tins.2019.05.006. PMID 31285047. S2CID 195834057.
↑ Rust R, Gantner C, Schwab ME (January 2019). "Pro- and antiangiogenic therapies: current status and clinical implications". FASEB Journal. 33 (1): 34–48. doi:10.1096/fj.201800640RR. PMID 30085886. S2CID 51937342.
↑ Sozmen EG, Rosenzweig S, Llorente IL, DiTullio DJ, Machnicki M, Vinters HV, et al. (December 2016). "Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice". Proceedings of the National Academy of Sciences of the United States of America. 113 (52): E8453–E8462. Bibcode:2016PNAS..113E8453S. doi:10.1073/pnas.1615322113. PMC 5206535. PMID 27956620.
↑ Rust R, Weber RZ, Grönnert L, Mulders G, Maurer MA, Hofer AS, et al. (December 2019). "Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke". Scientific Reports. 9 (1) 20040. Bibcode:2019NatSR...920040R. doi:10.1038/s41598-019-56634-1. PMC 6934709. PMID 31882970.
↑ Qin H, Pu HX, Li M, Ahmed S, Song J (December 2008). "Identification and structural mechanism for a novel interaction between a ubiquitin ligase WWP1 and Nogo-A, a key inhibitor for central nervous system regeneration". Biochemistry. 47 (51): 13647–13658. doi:10.1021/bi8017976. PMID 19035836.
1 2 Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y (November 2000). "A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity". Oncogene. 19 (50): 5736–5746. doi:10.1038/sj.onc.1203948. PMID 11126360.

Teng FY, Tang BL (August 2008). "Cell autonomous function of Nogo and reticulons: The emerging story at the endoplasmic reticulum". Journal of Cellular Physiology. 216 (2): 303–308. doi:10.1002/jcp.21434. PMID 18330888. S2CID 34163142.
Ng CE, Tang BL (March 2002). "Nogos and the Nogo-66 receptor: factors inhibiting CNS neuron regeneration". Journal of Neuroscience Research. 67 (5): 559–565. doi:10.1002/jnr.10134. PMID 11891768. S2CID 26061828.
Watari A, Yutsudo M (January 2003). "Multi-functional gene ASY/Nogo/RTN-X/RTN4: apoptosis, tumor suppression, and inhibition of neuronal regeneration". Apoptosis. 8 (1): 5–9. doi:10.1023/A:1021639016300. PMID 12510146. S2CID 37206000.
Schweigreiter R, Bandtlow CE (2006). "Nogo in the injured spinal cord". Journal of Neurotrauma. 23 (3–4): 384–396. doi:10.1089/neu.2006.23.384. PMID 16629624.
Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, et al. (December 1998). "Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 5 (6): 355–364. doi:10.1093/dnares/5.6.355. PMID 10048485.
Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, et al. (January 2000). "Inhibitor of neurite outgrowth in humans". Nature. 403 (6768): 383–384. doi:10.1038/35000287. PMID 10667780. S2CID 205004005.
Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, et al. (January 2000). "Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1". Nature. 403 (6768): 434–439. Bibcode:2000Natur.403..434C. doi:10.1038/35000219. PMID 10667796. S2CID 4388618.
Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, et al. (October 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research. 10 (10): 1546–1560. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Fournier AE, GrandPre T, Strittmatter SM (January 2001). "Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration". Nature. 409 (6818): 341–346. Bibcode:2001Natur.409..341F. doi:10.1038/35053072. PMID 11201742. S2CID 4404627.
Josephson A, Widenfalk J, Widmer HW, Olson L, Spenger C (June 2001). "NOGO mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury". Experimental Neurology. 169 (2): 319–328. doi:10.1006/exnr.2001.7659. PMID 11358445. S2CID 23996169.
Zhou ZM, Sha JH, Li JM, Lin M, Zhu H, Zhou YD, et al. (February 2002). "Expression of a novel reticulon-like gene in human testis". Reproduction. 123 (2). Cambridge, England: 227–234. doi:10.1530/rep.0.1230227. PMID 11866689.
GrandPré T, Li S, Strittmatter SM (May 2002). "Nogo-66 receptor antagonist peptide promotes axonal regeneration". Nature. 417 (6888): 547–551. Bibcode:2002Natur.417..547G. doi:10.1038/417547a. PMID 12037567. S2CID 4414714.
Hu WH, Hausmann ON, Yan MS, Walters WM, Wong PK, Bethea JR (April 2002). "Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP)". Journal of Neurochemistry. 81 (1): 36–45. doi:10.1046/j.1471-4159.2002.00788.x. PMID 12067236. S2CID 38794348.
Liu BP, Fournier A, GrandPré T, Strittmatter SM (August 2002). "Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor". Science. 297 (5584). New York, N.Y.: 1190–1193. Bibcode:2002Sci...297.1190L. doi:10.1126/science.1073031. PMID 12089450. S2CID 1357777.
Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de Tapia M, Pradat PF, et al. (August 2002). "Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis". Neurobiology of Disease. 10 (3): 358–365. doi:10.1006/nbdi.2002.0522. PMID 12270696. S2CID 45996722.
Taketomi M, Kinoshita N, Kimura K, Kitada M, Noda T, Asou H, et al. (October 2002). "Nogo-A expression in mature oligodendrocytes of rat spinal cord in association with specific molecules". Neuroscience Letters. 332 (1): 37–40. doi:10.1016/S0304-3940(02)00910-2. hdl:2433/148718. PMID 12377379. S2CID 13433362.
Li M, Shi J, Wei Z, Teng FY, Tang BL, Song J (September 2004). "Structural characterization of the human Nogo-A functional domains. Solution structure of Nogo-40, a Nogo-66 receptor antagonist enhancing injured spinal cord regeneration". European Journal of Biochemistry. 271 (17): 3512–3522. doi:10.1111/j.0014-2956.2004.04286.x. PMID 15317586.
Li M, Liu J, Song J (August 2006). "Nogo goes in the pure water: solution structure of Nogo-60 and design of the structured and buffer-soluble Nogo-54 for enhancing CNS regeneration". Protein Science. 15 (8): 1835–1841. doi:10.1110/ps.062306906. PMC 2242580. PMID 16877707.
Li M, Song J (July 2007). "The N- and C-termini of the human Nogo molecules are intrinsically unstructured: bioinformatics, CD, NMR characterization, and functional implications". Proteins. 68 (1): 100–108. doi:10.1002/prot.21385. PMID 17397058. S2CID 21507005.
Li M, Song J (August 2007). "Nogo-B receptor possesses an intrinsically unstructured ectodomain and a partially folded cytoplasmic domain". Biochemical and Biophysical Research Communications. 360 (1): 128–134. Bibcode:2007BBRC..360..128L. doi:10.1016/j.bbrc.2007.06.031. PMID 17585875.

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000115310 – Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020458 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[GrandPré_2000-5] 1 2 GrandPré T, Nakamura F, Vartanian T, Strittmatter SM (January 2000). "Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein". Nature. 403 (6768): 439–444. Bibcode:2000Natur.403..439G. doi:10.1038/35000226. PMID 10667797. S2CID 1926168.

[Yang_2000-6] 1 2 Yang J, Yu L, Bi AD, Zhao SY (June 2000). "Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 88 (1–2): 101–102. doi:10.1159/000015499. PMID 10773680. S2CID 37521141.

[entrez-7] 1 2 3 "Entrez Gene: RTN4 reticulon 4".

[Karnezis_2004-8] 1 2 Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, et al. (July 2004). "The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination". Nature Neuroscience. 7 (7): 736–744. doi:10.1038/nn1261. PMID 15184901. S2CID 9613584.

[Lee_2008-9] Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, et al. (March 2008). "Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength". The Journal of Neuroscience. 28 (11): 2753–2765. doi:10.1523/JNEUROSCI.5586-07.2008. PMC 6670664. PMID 18337405.; Lay summary in: "Stopping a receptor called 'nogo' boosts the synapses". EurekAlert!.

[Rust_2019-10] Rust R, Grönnert L, Gantner C, Enzler A, Mulders G, Weber RZ, et al. (July 2019). "Nogo-A targeted therapy promotes vascular repair and functional recovery following stroke". Proceedings of the National Academy of Sciences of the United States of America. 116 (28): 14270–14279. Bibcode:2019PNAS..11614270R. doi:10.1073/pnas.1905309116. PMC 6628809. PMID 31235580.

[Rust_2019_2-11] Rust R, Grönnert L, Weber RZ, Mulders G, Schwab ME (September 2019). "Refueling the Ischemic CNS: Guidance Molecules for Vascular Repair". Trends in Neurosciences. 42 (9): 644–656. doi:10.1016/j.tins.2019.05.006. PMID 31285047. S2CID 195834057.

[Rust_2019_3-12] Rust R, Gantner C, Schwab ME (January 2019). "Pro- and antiangiogenic therapies: current status and clinical implications". FASEB Journal. 33 (1): 34–48. doi:10.1096/fj.201800640RR. PMID 30085886. S2CID 51937342.

[Sozmen_2016-13] Sozmen EG, Rosenzweig S, Llorente IL, DiTullio DJ, Machnicki M, Vinters HV, et al. (December 2016). "Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice". Proceedings of the National Academy of Sciences of the United States of America. 113 (52): E8453–E8462. Bibcode:2016PNAS..113E8453S. doi:10.1073/pnas.1615322113. PMC 5206535. PMID 27956620.

[Rust_2019_4-14] Rust R, Weber RZ, Grönnert L, Mulders G, Maurer MA, Hofer AS, et al. (December 2019). "Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke". Scientific Reports. 9 (1) 20040. Bibcode:2019NatSR...920040R. doi:10.1038/s41598-019-56634-1. PMC 6934709. PMID 31882970.

[Qin_2008-15] Qin H, Pu HX, Li M, Ahmed S, Song J (December 2008). "Identification and structural mechanism for a novel interaction between a ubiquitin ligase WWP1 and Nogo-A, a key inhibitor for central nervous system regeneration". Biochemistry. 47 (51): 13647–13658. doi:10.1021/bi8017976. PMID 19035836.

[Tagami_2000-16] 1 2 Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y (November 2000). "A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity". Oncogene. 19 (50): 5736–5746. doi:10.1038/sj.onc.1203948. PMID 11126360.