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Reticulon 4

From Wikipedia, the free encyclopedia
(Redirected from RTN4)

RTN4
Identifiers
AliasesRTN4, 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 IDsOMIM: 604475; MGI: 1915835; GeneCards: RTN4
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

57142

68585

Ensembl

ENSG00000115310

ENSMUSG00000020458

UniProt

Q9NQC3

Q99P72

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 MbChr 11: 29.64 – 29.69 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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] 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.[7]

Structure

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Alternatively spliced transcript variants derived from both differential splicing and differential promoter usage have been identified and encode distinct isoforms of Nogo.[7] 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.[8]

Function

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Nogo has been identified as an inhibitor of neurite outgrowth specific to the central nervous system.[5][6]

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.[9]

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.[10][11][12]

Clinical significance

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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.[8][13]

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.[14]

Interactions

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

See also

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References

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  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. 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.
  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.
  7. 1 2 3 "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): 736–744. doi:10.1038/nn1261. PMID 15184901. S2CID 9613584.
  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!.
  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.
  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.
  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.
  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.
  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 (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.
  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.

Further reading

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