Reticulon 4 Explained

Reticulon 4, also known as Neurite outgrowth inhibitor or Nogo, is a protein that in humans is encoded by the RTN4 gene^{[1] [2] [3]} that 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.

This gene belongs to the family of reticulon-encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. The product of this gene is a potent neurite outgrowth inhibitor that may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified.^[3] There are three isoforms: Nogo A, B and C. Nogo-A has two known inhibitory domains including amino-Nogo, at the N-terminus and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in growth cone destruction.

Research suggests that blocking Nogo-A during neuronal damage (from diseases such as multiple sclerosis) will help to protect or restore the damaged neurons.^{[4] [5]} The investigation into the mechanisms of this protein presents a great potential for the treatment of auto-immune mediated demyelinating diseases and spinal cord injury regeneration. It has also been found to be a key player in the process whereby physical exercise enhances learning and memory processes in the brain.^[6] Nogo-A has also been shown to negatively regulate vascular growth and repair following ischemic stroke. Genetic deletion and antibody-mediated blockage of Nogo-A led to enhanced re-vascularization and functional recovery in an experimental mouse model of stroke.^{[7] [8] [9]} Moreover, vascular leakage, a major complication following stroke, was reduced following anti-Nogo-A antibody treatment.^[10]

Interactions

Reticulon 4 has been shown to interact with WWP1,^[11] BCL2-like 1^[12] and Bcl-2.^[12]

See also

• Reticulon 4 receptor

Further reading

• Teng FY, Tang BL . Cell autonomous function of Nogo and reticulons: The emerging story at the endoplasmic reticulum . Journal of Cellular Physiology . 216 . 2 . 303–8 . Aug 2008 . 18330888 . 10.1002/jcp.21434 . 34163142 .
• Ng CE, Tang BL . Nogos and the Nogo-66 receptor: factors inhibiting CNS neuron regeneration . Journal of Neuroscience Research . 67 . 5 . 559–65 . Mar 2002 . 11891768 . 10.1002/jnr.10134 . 26061828 . free .
• Watari A, Yutsudo M . Multi-functional gene ASY/Nogo/RTN-X/RTN4: apoptosis, tumor suppression, and inhibition of neuronal regeneration . Apoptosis . 8 . 1 . 5–9 . Jan 2003 . 12510146 . 10.1023/A:1021639016300 . 37206000 .
• Schweigreiter R, Bandtlow CE . Nogo in the injured spinal cord . Journal of Neurotrauma . 23 . 3–4 . 384–96 . 2006 . 16629624 . 10.1089/neu.2006.23.384 .
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 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 . 355–64 . Dec 1998 . 10048485 . 10.1093/dnares/5.6.355 . free .
• Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS . Inhibitor of neurite outgrowth in humans . Nature . 403 . 6768 . 383–4 . Jan 2000 . 10667780 . 10.1038/35000287 . 205004005 .
• Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME . Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1 . Nature . 403 . 6768 . 434–9 . Jan 2000 . 10667796 . 10.1038/35000219 . 2000Natur.403..434C . 4388618 .
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z . 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 . 1546–60 . Oct 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . Nov 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y . 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 . 5736–46 . Nov 2000 . 11126360 . 10.1038/sj.onc.1203948 . free .
• Fournier AE, GrandPre T, Strittmatter SM . Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration . Nature . 409 . 6818 . 341–6 . Jan 2001 . 11201742 . 10.1038/35053072 . 2001Natur.409..341F . 4404627 .
• Josephson A, Widenfalk J, Widmer HW, Olson L, Spenger C . NOGO mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury . Experimental Neurology . 169 . 2 . 319–28 . Jun 2001 . 11358445 . 10.1006/exnr.2001.7659 . 23996169 .
• Zhou ZM, Sha JH, Li JM, Lin M, Zhu H, Zhou YD, Wang LR, Zhu H, Wang YQ, Zhou KY . Expression of a novel reticulon-like gene in human testis . Reproduction . 123 . 2 . 227–34 . Feb 2002 . 11866689 . 10.1530/rep.0.1230227 . free .
• GrandPré T, Li S, Strittmatter SM . Nogo-66 receptor antagonist peptide promotes axonal regeneration . Nature . 417 . 6888 . 547–51 . May 2002 . 12037567 . 10.1038/417547a . 2002Natur.417..547G . 4414714 .
• Hu WH, Hausmann ON, Yan MS, Walters WM, Wong PK, Bethea JR . Identification and characterization of a novel Nogo-interacting mitochondrial protein (NIMP) . Journal of Neurochemistry . 81 . 1 . 36–45 . Apr 2002 . 12067236 . 10.1046/j.1471-4159.2002.00788.x . 38794348 .
• Liu BP, Fournier A, GrandPré T, Strittmatter SM . Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor . Science . 297 . 5584 . 1190–3 . Aug 2002 . 12089450 . 10.1126/science.1073031 . 2002Sci...297.1190L . 1357777 . free .
• Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de Tapia M, Pradat PF, Lacomblez L, Seihlan D, Prinjha R, Walsh FS, Meininger V, Loeffler JP . Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis . Neurobiology of Disease . 10 . 3 . 358–65 . Aug 2002 . 12270696 . 10.1006/nbdi.2002.0522 . 45996722 .
• Taketomi M, Kinoshita N, Kimura K, Kitada M, Noda T, Asou H, Nakamura T, Ide C . Nogo-A expression in mature oligodendrocytes of rat spinal cord in association with specific molecules . Neuroscience Letters . 332 . 1 . 37–40 . Oct 2002 . 12377379 . 10.1016/S0304-3940(02)00910-2 . 2433/148718 . 13433362 . free .
• Li M, Shi J, Wei Z, Teng FY, Tang BL, Song J . 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 . 3512–22 . Sep 2004 . 15317586 . 10.1111/j.0014-2956.2004.04286.x . free .
• Li M, Liu J, Song J . 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 . 1835–41 . Aug 2006 . 16877707 . 2242580 . 10.1110/ps.062306906 .
• Li M, Song J . The N- and C-termini of the human Nogo molecules are intrinsically unstructured: bioinformatics, CD, NMR characterization, and functional implications . Proteins . 68 . 1 . 100–8 . Jul 2007 . 17397058 . 10.1002/prot.21385 . 21507005 .
• Li M, Song J . Nogo-B receptor possesses an intrinsically unstructured ectodomain and a partially folded cytoplasmic domain . Biochemical and Biophysical Research Communications . 360 . 1 . 128–34 . Aug 2007 . 17585875 . 10.1016/j.bbrc.2007.06.031 .

Notes and References

1. GrandPré T, Nakamura F, Vartanian T, Strittmatter SM . Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein . Nature . 403 . 6768 . 439–44 . Jan 2000 . 10667797 . 10.1038/35000226 . 2000Natur.403..439G . 1926168 .
2. Yang J, Yu L, Bi AD, Zhao SY . Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping . Cytogenetics and Cell Genetics . 88 . 1–2 . 101–2 . June 2000 . 10773680 . 10.1159/000015499 . 37521141 .
3. Web site: Entrez Gene: RTN4 reticulon 4.
4. Karnezis T, Mandemakers W, McQualter JL, Zheng B, Ho PP, Jordan KA, Murray BM, Barres B, Tessier-Lavigne M, Bernard CC . 6 . The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination . Nature Neuroscience . 7 . 7 . 736–44 . July 2004 . 15184901 . 10.1038/nn1261 . 9613584 .
5. Sozmen EG, Rosenzweig S, Llorente IL, DiTullio DJ, Machnicki M, Vinters HV, Havton LA, Giger RJ, Hinman JD, Carmichael ST . 6 . 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 . December 2016 . 27956620 . 5206535 . 10.1073/pnas.1615322113 . 2016PNAS..113E8453S . free .
6. Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, Yeh HH, Shrager P, Giger RJ . Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength . The Journal of Neuroscience . 28 . 11 . 2753–65 . March 2008 . 18337405 . 6670664 . 10.1523/JNEUROSCI.5586-07.2008.
   • 18 March 2008 . Stopping a receptor called 'nogo' boosts the synapses . EurekAlert! .
7. Rust R, Grönnert L, Gantner C, Enzler A, Mulders G, Weber RZ, Siewert A, Limasale YD, Meinhardt A, Maurer MA, Sartori AM, Hofer AS, Werner C, Schwab ME . 6 . 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 . July 2019 . 31235580 . 10.1073/pnas.1905309116 . 6628809 . 2019PNAS..11614270R . free .
8. Rust . R . Grönnert . L . Weber . RZ . Mulders . G . Schwab . ME . Refueling the Ischemic CNS: Guidance Molecules for Vascular Repair. . Trends in Neurosciences . September 2019 . 42 . 9 . 644–656 . 10.1016/j.tins.2019.05.006 . 31285047. 195834057 .
9. Rust . R . Gantner . C . Schwab . ME . Pro- and antiangiogenic therapies: current status and clinical implications. . FASEB Journal . January 2019 . 33 . 1 . 34–48 . 10.1096/fj.201800640RR . 30085886. 51937342 . free .
10. Rust R, Weber RZ, Grönnert L, Mulders G, Maurer MA, Hofer AS, Sartori AM, Schwab ME . 6 . Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke . Scientific Reports . 9 . 1 . 20040 . December 2019 . 31882970 . 10.1038/s41598-019-56634-1 . 6934709 . 2019NatSR...920040R .
11. Qin H, Pu HX, Li M, Ahmed S, Song J . 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 . 13647–58 . Dec 2008 . 19035836 . 10.1021/bi8017976 .
12. Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y . 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 . 5736–46 . Nov 2000 . 11126360 . 10.1038/sj.onc.1203948 . free .