Biology:Reticulon 4

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[4]

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

References

  1. ↑ "Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein". Nature 403 (6768): 439–44. Jan 2000. doi:10.1038/35000226. PMID 10667797. Bibcode: 2000Natur.403..439G. 
  2. ↑ "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. doi:10.1159/000015499. PMID 10773680. 
  3. ↑ 3.0 3.1 "Entrez Gene: RTN4 reticulon 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57142. 
  4. ↑ 4.0 4.1 "The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination". Nature Neuroscience 7 (7): 736–44. July 2004. doi:10.1038/nn1261. PMID 15184901. 
  5. ↑ "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. doi:10.1073/pnas.1615322113. PMID 27956620. Bibcode: 2016PNAS..113E8453S. 
  6. ↑ "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. doi:10.1523/JNEUROSCI.5586-07.2008. PMID 18337405. 
    • "Stopping a receptor called 'nogo' boosts the synapses". EurekAlert! (Press release). 18 March 2008.
  7. ↑ "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. doi:10.1073/pnas.1905309116. PMID 31235580. Bibcode: 2019PNAS..11614270R. 
  8. ↑ 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. 
  9. ↑ 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. 
  10. ↑ "Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke". Scientific Reports 9 (1): 20040. December 2019. doi:10.1038/s41598-019-56634-1. PMID 31882970. Bibcode: 2019NatSR...920040R. 
  11. ↑ "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. doi:10.1021/bi8017976. PMID 19035836. 
  12. ↑ 12.0 12.1 "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. doi:10.1038/sj.onc.1203948. PMID 11126360. 

Further reading




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