Reticulon 4

Last updated
RTN4
Protein RTN4 PDB 2g31.png
Available structures
PDB Ortholog search: PDBe RCSB
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; HomoloGene: 10743; GeneCards: RTN4; OMA:RTN4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_024226
NM_194051
NM_194052
NM_194053
NM_194054

RefSeq (protein)

NP_077188
NP_918940
NP_918941
NP_918942
NP_918943

Location (UCSC) Chr 2: 54.97 – 55.11 Mb Chr 11: 29.64 – 29.69 Mb
PubMed search [3] [4]
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 [5] [6] [7] 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. [7] 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. [8]

Research suggests that blocking Nogo-A during neuronal damage (from diseases such as multiple sclerosis) will help to protect or restore the damaged neurons. [8] [9] 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. [10] 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. [11] [12] [13] Moreover, vascular leakage, a major complication following stroke, was reduced following anti-Nogo-A antibody treatment. [14]

Interactions

Reticulon 4 has been shown to interact with WWP1, [15] BCL2-like 1 [16] and Bcl-2. [16]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115310 Ensembl, May 2017
  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.
  5. GrandPré T, Nakamura F, Vartanian T, Strittmatter SM (Jan 2000). "Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein". Nature. 403 (6768): 439–44. Bibcode:2000Natur.403..439G. doi:10.1038/35000226. PMID   10667797. S2CID   1926168.
  6. 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): 101–2. doi:10.1159/000015499. PMID   10773680. S2CID   37521141.
  7. 1 2 "Entrez Gene: RTN4 reticulon 4".
  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): 736–44. doi:10.1038/nn1261. PMID   15184901. S2CID   9613584.
  9. 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.
  10. Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, Yeh HH, Shrager P, Giger RJ (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): 2753–65. doi:10.1523/JNEUROSCI.5586-07.2008. PMC   6670664 . PMID   18337405.
  11. 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.
  12. 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.
  13. 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.
  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.
  15. Qin H, Pu HX, Li M, Ahmed S, Song J (Dec 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): 13647–58. doi:10.1021/bi8017976. PMID   19035836.
  16. 1 2 Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y (Nov 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): 5736–46. doi: 10.1038/sj.onc.1203948 . PMID   11126360.

Further reading