RTN4 (reticulon 4)

2007-01-01   Masuo Yutsudo 

Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, Japan

Identity

HGNC
LOCATION
2p16.1
IMAGE
Atlas Image
LEGEND
Local order.
LOCUSID
ALIAS
ASY,NI220/250,NOGO,NSP,NSP-CL,Nbla00271,Nbla10545,RTN-X,RTN4-A,RTN4-B1,RTN4-B2,RTN4-C
FUSION GENES

DNA/RNA

Atlas Image
Genomic structure and transcriptional isoforms.

Description

The RTN4 gene spans about 75kb, and contains 9 major exons and several different cap sites (Fig. 2a).

Transcription

Three major, RTN4-A, B1 and C, (Fig. 2b) and several minor transcriptional isoforms result from alternative splicing and/or differential promoter usage. Although RTN4 mRNA is ubiquitously expressed, the expression of isoforms is tissue-specific, for example, RTN4-A and C in brain, RTN4-C in muscle, and RTN4-B1 in many other tissues.

Proteins

Description

Proteins with different sizes are synthesized from different mRNA isoforms: RTN4-A, 129.9 kDa (1192 amino acids); RTN4-B1, 40.3 kDa (373 amino acids); RTN4-B2, 42.3 kDa (392 amino acids); RTN4-C, 22.4 kDa (199 amino acids). All RTN4 protein isoforms retain a common C-terminal domain containing two trans-membrane domains and an endoplasmic reticulum (ER)-retrieval motif.

Expression

Ubiquitously expressed (see Transcription).

Localisation

RTN4 protein localizes predominantly in the ER and, to a lesser extent, in cytoplasmic membrane.

Function

Although definitive functional mechanisms of RTN4 have not yet been clarified, RTN4 protein interacts with several other proteins, including RTN1, RTN3, DP1/Yop1p, BACE1, and Nogo receptor (NogoR). Interaction with DP1/Yop1p, an ER membrane protein, may be necessary for maintenance or stabilization of tubular ER. Binding with BACE1 (beta-amyloid converting enzyme 1) results in reduction in BACE1 activity and production of amyloid-beta. RTN4 also interacts with NogoR, and may lead to activation of RhoA and inhibition of neuronal regeneration in central nervous system. Further, overexpression of RTN4 may cause ER stress and apoptosis in certain cells.

Homology

Four reticulon family members (RTN1, RTN2, RTN3 and RTN4) have been identified. They possess a highly conserved C-terminal domain named reticulon homology domain.

Implicated in

Entity name
Various cancers.
Note
Down-regulation of RTN4 expression was observed in small cell lung carcinomas and adult T-cell leukemia/lymphomas, and RTN3, one of RTN4 interacting proteins, was over-expressed in astrocytomas, suggesting involvement of RTN4 (and RTN3) in certain types of tumorigenesis. However, increased incidence of tumor formation has not been observed in RTN4 knock out mice.
RTN4 is also suspected to involve in schizophrenia and neuronal degenerative diseases.

Bibliography

Pubmed IDLast YearTitleAuthors
150345702004A new role for Nogo as a regulator of vascular remodeling.Acevedo L et al
106677962000Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.Chen MS et al
169051192006Human Nogo-C overexpression induces HEK293 cell apoptosis via a mechanism that involves JNK-c-Jun pathway.Chen Y et al
122706962002Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis.Dupuis L et al
112017422001Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.Fournier AE et al
106677972000Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein.GrandPré T et al
152867842004Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation.He W et al
149869272004Overexpression of human reticulon 3 (hRTN3) in astrocytoma.Huang X et al
127188542003Axon regeneration in young adult mice lacking Nogo-A/B.Kim JE et al
166871402006ER stress triggers apoptosis induced by Nogo-B/ASY overexpression.Kuang E et al
114941212001Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer.Li Q et al
169655502006Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein.Murayama KS et al
124259462002Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert.Novak G et al
170229552006Nogo A, B and C expression in schizophrenia, depression and bipolar frontal cortex, and correlation of Nogo expression with CAA/TATC polymorphism in 3'-UTR.Novak G et al
124880972003Genomic structure and functional characterisation of the promoters of human and mouse nogo/rtn4.Oertle T et al
126677562003Nogo and its paRTNers.Oertle T et al
106677802000Inhibitor of neurite outgrowth in humans.Prinjha R et al
128118242003Pro-apoptotic ASY/Nogo-B protein associates with ASYIP.Qi B et al
160954392005Nogo-B is a new physiological substrate for MAPKAP-K2.Rousseau S et al
167232742006The Nogo receptor complex: confining molecules to molecular mechanisms.Schwab JM et al
166460682006Down-regulation of ASY/Nogo transcription associated with progression of adult T-cell leukemia/lymphoma.Shimakage M et al
127188552003Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury.Simonen M et al
155320242004Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia.Sinibaldi L et al
111263602000A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity.Tagami S et al
164697032006A class of membrane proteins shaping the tubular endoplasmic reticulum.Voeltz GK et al
125101462003Multi-functional gene ASY/Nogo/RTN-X/RTN4: apoptosis, tumor suppression, and inhibition of neuronal regeneration.Watari A et al
165059742006Reticulon proteins: emerging players in neurodegenerative diseases.Yan R et al
107736802000Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping.Yang J et al
156473572005Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo.Zheng B et al
127188562003Lack of enhanced spinal regeneration in Nogo-deficient mice.Zheng B et al

Other Information

Locus ID:

NCBI: 57142
MIM: 604475
HGNC: 14085
Ensembl: ENSG00000115310

Variants:

dbSNP: 57142
ClinVar: 57142
TCGA: ENSG00000115310
COSMIC: RTN4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000115310ENST00000317610Q9NQC3
ENSG00000115310ENST00000337526Q9NQC3
ENSG00000115310ENST00000357376Q9NQC3
ENSG00000115310ENST00000357732Q9NQC3
ENSG00000115310ENST00000394609Q9NQC3
ENSG00000115310ENST00000394611Q9NQC3
ENSG00000115310ENST00000402434F8W914
ENSG00000115310ENST00000404909Q9NQC3
ENSG00000115310ENST00000405240Q9NQC3
ENSG00000115310ENST00000427710C9J685
ENSG00000115310ENST00000438462H7C106
ENSG00000115310ENST00000486085A0A0U1RQR6

Expression (GTEx)

0
50
100
150
200
250
300
350

Pathways

PathwaySourceExternal ID
Alzheimer's diseaseKEGGko05010
Alzheimer's diseaseKEGGhsa05010
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
p75NTR regulates axonogenesisREACTOMER-HSA-193697
Axonal growth inhibition (RHOA activation)REACTOMER-HSA-193634

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
185839792008Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.395
150345702004A new role for Nogo as a regulator of vascular remodeling.85
216975312011The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension.71
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
182349032008The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism.61
168353002006Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells.57
168353002006Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells.57
191655272009Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.56
198899962009Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis.37
195872712009Reassessment of corticospinal tract regeneration in Nogo-deficient mice.35

Citation

Masuo Yutsudo

RTN4 (reticulon 4)

Atlas Genet Cytogenet Oncol Haematol. 2007-01-01

Online version: http://atlasgeneticsoncology.org/gene/42182/rtn4