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RTN4 (reticulon 4)

Written2007-01Masuo Yutsudo
Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, Japan

(Note : for Links provided by Atlas : click)


HGNC (Hugo) RTN4
HGNC Alias symbNSP-CL
LocusID (NCBI) 57142
Atlas_Id 42182
Location 2p16.1  [Link to chromosome band 2p16]
Location_base_pair Starts at 54972191 and ends at 55049156 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping RTN4.png]
Local_order Between FLJ42562 and FLJ31438.
  Local order.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADAM12 (10q26.2)::RTN4 (2p16.1)AFF3 (2q11.2)::RTN4 (2p16.1)ANAPC4 (4p15.2)::RTN4 (2p16.1)
CBFA2T2 (20q11.21)::RTN4 (2p16.1)CRY2 (11p11.2)::RTN4 (2p16.1)FRMD6 (14q22.1)::RTN4 (2p16.1)
ICAM1 (19p13.2)::RTN4 (2p16.1)KARS (16q23.1)::RTN4 (2p16.1)LDAH (2p24.1)::RTN4 (2p16.1)
RGL1 (1q25.3)::RTN4 (2p16.1)RTN4 (2p16.1)::ANAPC4 (4p15.2)RTN4 (2p16.1)::ATP5G2 (12q13.13)
RTN4 (2p16.1)::ENTPD1 (10q24.1)RTN4 (2p16.1)::MITD1 (2q11.2)RTN4 (2p16.1)::RTN4 (2p16.1)
RTN4 (2p16.1)::UTP3 (4q13.3)TIMM17A (1q32.1)::RTN4 (2p16.1)


  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.


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 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.


A new role for Nogo as a regulator of vascular remodeling.
Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P, Strittmatter SM, Sessa WC
Nature medicine. 2004 ; 10 (4) : 382-388.
PMID 15034570
Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.
Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME
Nature. 2000 ; 403 (6768) : 434-439.
PMID 10667796
Human Nogo-C overexpression induces HEK293 cell apoptosis via a mechanism that involves JNK-c-Jun pathway.
Chen Y, Tang X, Cao X, Chen H, Zhang X
Biochemical and biophysical research communications. 2006 ; 348 (3) : 923-928.
PMID 16905119
Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis.
Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de Tapia M, Pradat PF, Lacomblez L, Seihlan D, Prinjha R, Walsh FS, Meininger V, Loeffler JP
Neurobiology of disease. 2002 ; 10 (3) : 358-365.
PMID 12270696
Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.
Fournier AE, GrandPre T, Strittmatter SM
Nature. 2001 ; 409 (6818) : 341-346.
PMID 11201742
Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein.
GrandPré T, Nakamura F, Vartanian T, Strittmatter SM
Nature. 2000 ; 403 (6768) : 439-444.
PMID 10667797
Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation.
He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R
Nature medicine. 2004 ; 10 (9) : 959-965.
PMID 15286784
Overexpression of human reticulon 3 (hRTN3) in astrocytoma.
Huang X, Yang H, Zhou Y, Liu J, Yin B, Peng X, Qiang B, Yuan J
Clinical neuropathology. 2004 ; 23 (1) : 1-7.
PMID 14986927
Axon regeneration in young adult mice lacking Nogo-A/B.
Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM
Neuron. 2003 ; 38 (2) : 187-199.
PMID 12718854
ER stress triggers apoptosis induced by Nogo-B/ASY overexpression.
Kuang E, Wan Q, Li X, Xu H, Zou T, Qi Y
Experimental cell research. 2006 ; 312 (11) : 1983-1988.
PMID 16687140
Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer.
Li Q, Qi B, Oka K, Shimakage M, Yoshioka N, Inoue H, Hakura A, Kodama K, Stanbridge EJ, Yutsudo M
Oncogene. 2001 ; 20 (30) : 3929-3936.
PMID 11494121
Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein.
Murayama KS, Kametani F, Saito S, Kume H, Akiyama H, Araki W
The European journal of neuroscience. 2006 ; 24 (5) : 1237-1244.
PMID 16965550
Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert.
Novak G, Kim D, Seeman P, Tallerico T
Brain research. Molecular brain research. 2002 ; 107 (2) : 183-189.
PMID 12425946
Nogo 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, Tallerico T
Brain research. 2006 ; 1120 (1) : 161-171.
PMID 17022955
Genomic structure and functional characterisation of the promoters of human and mouse nogo/rtn4.
Oertle T, Huber C, van der Putten H, Schwab ME
Journal of molecular biology. 2003 ; 325 (2) : 299-323.
PMID 12488097
Nogo and its paRTNers.
Oertle T, Schwab ME
Trends in cell biology. 2003 ; 13 (4) : 187-194.
PMID 12667756
Inhibitor of neurite outgrowth in humans.
Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS
Nature. 2000 ; 403 (6768) : 383-384.
PMID 10667780
Pro-apoptotic ASY/Nogo-B protein associates with ASYIP.
Qi B, Qi Y, Watari A, Yoshioka N, Inoue H, Minemoto Y, Yamashita K, Sasagawa T, Yutsudo M
Journal of cellular physiology. 2003 ; 196 (2) : 312-318.
PMID 12811824
Nogo-B is a new physiological substrate for MAPKAP-K2.
Rousseau S, Peggie M, Campbell DG, Nebreda AR, Cohen P
The Biochemical journal. 2005 ; 391 (Pt 2) : 433-440.
PMID 16095439
The Nogo receptor complex: confining molecules to molecular mechanisms.
Schwab JM, Tuli SK, Failli V
Trends in molecular medicine. 2006 ; 12 (7) : 293-297.
PMID 16723274
Down-regulation of ASY/Nogo transcription associated with progression of adult T-cell leukemia/lymphoma.
Shimakage M, Inoue N, Ohshima K, Kawahara K, Oka T, Yasui K, Matsumoto K, Inoue H, Watari A, Higashiyama S, Yutsudo M
International journal of cancer. Journal international du cancer. 2006 ; 119 (7) : 1648-1653.
PMID 16646068
Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury.
Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, Christ F, Sansig G, van der Putten H, Schwab ME
Neuron. 2003 ; 38 (2) : 201-211.
PMID 12718855
Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia.
Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A, Paloscia C, Spalletta G, Caltagirone C, Pizzuti A, Dallapiccola B
Human mutation. 2004 ; 24 (6) : 534-535.
PMID 15532024
A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity.
Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y
Oncogene. 2000 ; 19 (50) : 5736-5746.
PMID 11126360
A class of membrane proteins shaping the tubular endoplasmic reticulum.
Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA
Cell. 2006 ; 124 (3) : 573-586.
PMID 16469703
Multi-functional gene ASY/Nogo/RTN-X/RTN4: apoptosis, tumor suppression, and inhibition of neuronal regeneration.
Watari A, Yutsudo M
Apoptosis : an international journal on programmed cell death. 2003 ; 8 (1) : 5-9.
PMID 12510146
Reticulon proteins: emerging players in neurodegenerative diseases.
Yan R, Shi Q, Hu X, Zhou X
Cellular and molecular life sciences : CMLS. 2006 ; 63 (7-8) : 877-889.
PMID 16505974
Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14-->2p13 by radiation hybrid mapping.
Yang J, Yu L, Bi AD, Zhao SY
Cytogenetics and cell genetics. 2000 ; 88 (1-2) : 101-102.
PMID 10773680
Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo.
Zheng B, Atwal J, Ho C, Case L, He XL, Garcia KC, Steward O, Tessier-Lavigne M
Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (4) : 1205-1210.
PMID 15647357
Lack of enhanced spinal regeneration in Nogo-deficient mice.
Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M
Neuron. 2003 ; 38 (2) : 213-224.
PMID 12718856


This paper should be referenced as such :
Yutsudo, M
RTN4 (reticulon 4)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):128-130.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)RTN4   14085
Entrez_Gene (NCBI)RTN4    reticulon 4
AliasesASY; NI220/250; NOGO; NSP; 
NSP-CL; Nbla00271; Nbla10545; RTN-X; RTN4-A; RTN4-B1; RTN4-B2; RTN4-C
GeneCards (Weizmann)RTN4
Ensembl hg19 (Hinxton)ENSG00000115310 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000115310 [Gene_View]  ENSG00000115310 [Sequence]  chr2:54972191-55049156 [Contig_View]  RTN4 [Vega]
ICGC DataPortalENSG00000115310
TCGA cBioPortalRTN4
AceView (NCBI)RTN4
Genatlas (Paris)RTN4
SOURCE (Princeton)RTN4
Genetics Home Reference (NIH)RTN4
Genomic and cartography
GoldenPath hg38 (UCSC)RTN4  -     chr2:54972191-55049156 -  2p16.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RTN4  -     2p16.1   [Description]    (hg19-Feb_2009)
GoldenPathRTN4 - 2p16.1 [CytoView hg19]  RTN4 - 2p16.1 [CytoView hg38]
Genome Data Viewer NCBIRTN4 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB015639 AB020693 AB040462 AB040463 AB073351
RefSeq transcript (Entrez)NM_001321859 NM_001321860 NM_001321861 NM_001321862 NM_001321863 NM_001321904 NM_007008 NM_020532 NM_153828 NM_207520 NM_207521
Consensus coding sequences : CCDS (NCBI)RTN4
Gene ExpressionRTN4 [ NCBI-GEO ]   RTN4 [ EBI - ARRAY_EXPRESS ]   RTN4 [ SEEK ]   RTN4 [ MEM ]
Gene Expression Viewer (FireBrowse)RTN4 [ Firebrowse - Broad ]
GenevisibleExpression of RTN4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57142
GTEX Portal (Tissue expression)RTN4
Human Protein AtlasENSG00000115310-RTN4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)RTN4
Human Protein Atlas [tissue]ENSG00000115310-RTN4 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed223 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:27:21 CEST 2021

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