Disease relevance of RTN4

• Nogo-A and nogo receptor expression in demyelinating lesions of multiple sclerosis [1].
• A myelin-associated neurite outgrowth inhibitor, Nogo-A, plays a key role in inhibition of axonal regeneration following injury and ischemia in the central nervous system (CNS) [1].
• We showed in this report that substratum adherence and migration by human U87MG glioma cells in culture were significantly attenuated by the extracellular domains of Nogo-A (Nogo-66) and the myelin-associated glycoprotein (MAG) [2].
• Antibodies against Nogo-A stain CNS myelin and oligodendrocytes and allow dorsal root ganglion neurites to grow on CNS myelin and into optic nerve explants [3].
• Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis [4].

Psychiatry related information on RTN4

• Expression pattern of NOGO and NgR genes during human development [5].
• The Nogo gene maps to 2p14-p13, a region consistently associated with schizophrenia and bipolar disorder [6].
• The possibility that the Nogo system contributes to pathologic and compensatory plasticity in Alzheimer's Disease is considered [7].
• The experiment was repeated for one of the subjects using a 151 whole-head biomagnetometer; the same auditory GO/NOGO choice reaction time paradigm as in the first experiment was used, extended to include repetitions of identical runs and additional control conditions [8].
• Individual differences in error processing: a review and reanalysis of three event-related fMRI studies using the GO/NOGO task [9].

High impact information on RTN4

• Coupled with recent insights into the mechanism by which Nogo inhibits axonal regeneration, this discovery may inspire new treatments for central nervous system injuries and neurodegenerative diseases [10].
• In brain, BACE1 mainly colocalizes with RTN3 in neurons, whereas RTN4 is more enriched in oligodendrocytes [11].
• Although Nogo-A has been identified in the central nervous system as an inhibitor of axonal regeneration, the peripheral roles of Nogo isoforms remain virtually unknown [12].
• In addition to myelin-associated glycoprotein (MAG) and Nogo-A, available evidence suggests the existence of additional inhibitors in CNS myelin [13].
• Analysis of Nogo-A has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes [14].

Biological context of RTN4

• Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping [15].
• We have previously shown that ectopic expression of the ASY/Nogo-B gene induced apoptosis in various cancer cell lines [16].
• To investigate the mechanism of ASY-induced apoptosis or inhibition of neuronal regeneration, we cloned a cDNA for the ASY-interacting protein from the human cDNA library using the yeast two-hybrid method, and obtained a cDNA we designated as ASYIP [16].
• In mammalian genomes, transcripts are produced from four genes, rtn1 to rtn4, under the regulation of tissue or cell-type-specific expression [17].
• Several residues defining the structural epitope of NgR involved in interaction with Nogo were subsequently confirmed by alanine scanning mutagenesis [18].

Anatomical context of RTN4

• Over the last few years, the widely distributed family of reticulons (RTNs) is receiving renewed interest because of the implication of RTN4/Nogo in neurite regeneration [19].
• Nogo-A, a splice variant of the ASY, has been reported to have an inhibitory effect on neuronal regeneration in the central nervous system [16].
• Nogo is a potent inhibitor of regeneration following spinal cord injury [20].
• Despite predominant localization in the endoplasmic reticulum, Nogo on the cell surface appears to play a critical role as an inhibitory molecule for axonal growth and regeneration in humans and rodents [17].
• Messenger RNA encoding Nogo is expressed in oligodendrocytes and central and peripheral neurons, but not in astrocytes or Schwann cells [21].

Associations of RTN4 with chemical compounds

• The 66-amino acid extracellular domain of Nogo (Nogo-66) interacts with a high-affinity receptor (NgR), a glycosylphosphatidylinositol (GPI)-linked protein with multiple leucine-rich repeats [22].
• By Northern blot analysis, the levels of Nogo-A mRNA were elevated markedly in NTera2 cells following RA-induced neuronal differentiation, accompanied by an increased expression of the neurite growth-associated protein GAP-43 mRNA [23].
• The relative contribution of Nogo, myelin-associated glycoprotein, chondroitin sulfate proteoglycan and oligodendrocyte myelin glycoprotein to myelin inhibition can be assessed [24].
• Our previous study demonstrated that the overexpression of reticulon 3 (RTN3, also named HAP, homologue of ASY protein) caused apoptosis with the depletion of ER Ca(2+) stores [25].
• No obvious change of nogo expression was detected in kainic acid exposed animals [26].

Physical interactions of RTN4

• By applying this method of "affinity fingerprinting" to the NgR ligand binding domain we were able to detect a distinct region important for binding to Nogo [18].

Co-localisations of RTN4

• By immunofluorescence analysis, the ASYIP protein was shown to be co-localized with ASY in the ER [16].

Regulatory relationships of RTN4

• In developing dental germs, NgR was more strongly expressed than NOGO at 16 and 21 weeks [5].
• Our data indicated RTN4-C gene was expressed differently in hepatocellular carcinoma and its paracancerous tissues [27].

Other interactions of RTN4

• We report Nogo-A as an oligodendroglial component congregating and interacting with the Caspr-F3 complex at paranodes [28].
• Recent evidence suggests that the expression of certain myelin-associated proteins (e.g. Nogo-A) can be regulated by synaptic activity or by over-expression after neural lesions in brain syndromes such as temporal lobe epilepsy [29].
• Nogo-A expression in the human hippocampus in normal aging and in Alzheimer disease [29].
• In this study, using quantitative reverse transcriptase-polymerase chain reaction RT-PCR, expression of neuregulin-1 mitogen/survival factors and the axonal growth regulator Nogo was quantified in OECs and compared with other non-neuronal cells [30].
• Vesicles were found positive for the proapoptotic molecule, Fas-ligand (Fas-L), and for the B isoform of Nogo protein, a myelin component with inhibitory effects on neurons [31].

Analytical, diagnostic and therapeutic context of RTN4

• By reverse transcriptase-polymerase chain reaction analysis, the constitutive expression of Nogo-A, the longest isoform of three distinct Nogo transcripts and NgR mRNA was identified in a wide variety of human neural and non-neural cell lines [23].
• We investigated the expression of the genes encoding Nogo and its receptor, NgR, between weeks eight and 23 of human embryonic development, by quantitative radioactive in situ hybridization [5].
• Nogo A-like immunoreactivity increased after denervation and was also present in intramuscular nerves in both innervated and denervated muscle [32].
• Western blots and immunohistochemistry confirmed the presence of Nogo A-like and Nogo B-like immunoreactivity in muscle [32].
• Similar elevations in Nogo-A mRNA and protein levels were determined by quantitative RT-PCR and Western blotting [33].

References