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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review RTN4 (reticulon 4) Masuo Yutsudo Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, Japan Published in Atlas Database: January 2007 Online updated version: http://AtlasGeneticsOncology.org/Genes/RTN4ID42182ch2p16.html DOI: 10.4267/2042/38416 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology NSP; NSP-CL; Nbla00271; Nbla10545; RTN-X; RTN4-A; RTN4-B1; RTN4-B2; RTN4-C Location: 2p16.3 Local order: Between FLJ42562 and FLJ31438. Identity Hugo: RTN4 Other names: ASY; NI220/250; NOGO; NOGO-A; Fig 1. Local order. Fig 2. Genomic structure and transcriptional isoforms. Atlas Genet Cytogenet Oncol Haematol. 2007;11(2) 128 RTN4 (reticulon 4) Yutsudo M DNA/RNA Implicated in Description Various cancers The RTN4 gene spans about 75kb, and contains 9 major exons and several different cap sites (Fig. 2a). 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. 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. References Protein Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME. Nogo-A is a myelinassociated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 2000;403:434-439. 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. GrandPré T, Nakamura F, Vartanian T, Strittmatter SM. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 2000;403:439-444. Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS. Inhibitor of neurite outgrowth in humans. Nature 2000;403:383-384. Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y. A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity. Oncogene 2000;19:5736-5746. Expression Ubiquitously expressed (see Transcription). Yang J, Yu L, Bi AD, Zhao SY. Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14---2p13 by radiation hybrid mapping. Cytogenet Cell Genet 2000;88:101102. Localisation RTN4 protein localizes predominantly in the ER and, to a lesser extent, in cytoplasmic membrane. Fournier AE, GrandPré T, Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 2001;409:341-346. Function Li Q, Qi B, Oka K, Shimakage M, Yoshioka N, Inoue H, Hakura A, Kodama K, Stanbridge EJ, Yutsudo M. Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer. Oncogene 2001;20:3929-3936. 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. 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. Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis. Neurobiol Dis 2002;10:358-365. Novak G, Kim D, Seemen P, Tallerico T. Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Brain Res Mol Brain Res 2002;107:183-189. Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 2003;38:187-190. Homology Oertle T, Huber C, van der Putten H, Schwab ME. Genomic structure and functional characterization of the promoters of human and mouse nogo/rtn4. J Mol Biol 2003;325:299-323. Four reticulon family members (RTN1, RTN2, RTN3 and RTN4) have been identified. They possess a highly conserved C-terminal domain named reticulon homology domain. Atlas Genet Cytogenet Oncol Haematol. 2007;11(2) Oertle T, Schwab ME. Nogo and its partners. Trends Cell Biol 2003;13:187-194. (Review). 129 RTN4 (reticulon 4) Yutsudo M Qi B, Qi Y, Watari A, Yoshioka N, Inoue H, Minemoto Y, Yamashita K, Sasagawa T, Yutsudo M. Pro-apoptotic ASY/Nogo-B protein associates with ASYIP. J Cell Physiol 2003;196:312-318. corticospinal tract regeneration in vivo. Proc Natl Acad Sci USA 2005;102:1205-1210. Chen Y, Tang X, Cao X, Chen H, Zhang X. Human Nogo-C overexpression induces HEK293 cell apoptosis via a mechanism that involves JNK-c-Jun pathway. Biochem Biophys Res Commun 2006;348:923-928. Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, Christ F, Sansig G, van der Putten H, Schwab ME. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 2003;38:201-211. Kuang E, Wan Q, Li X, Zou T, Qi Y. ER stress triggers apoptosis induced by Nogo-B/ASY overexpression. Exp Cell Res 2006;312:1983-1988. Watari A, Yutsudo M. Multi-functional gene ASY/Nogo/RTNX/RTN4: Apoptosis, tumor suppression, and inhibition of neuronal regeneration. Apoptosis 2003;8:5-9. (Review). Murayama KS, Kametani F, Saito S, Kume H, Akiyama H, Araki W. Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein. Eur J Neurosci 2006;24:1237-1244. Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 2003;38:213-224. Novak G, Tallerico T. Nogo A, B and C expression in schizophrenia, depression and bipolar cortex, and correlation of Nogo expression with CAA/TATC polymorphism in 3-UTR. Brain Res 2006;1120:161-171. Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P, Strittmatter SM, Sessa WC. A new role for Nogo as a regulator of vascular remodeling. Nat Med 2004;10:382-388. Schwab JM, Tuli SK, Failli V. The Nogo receptor complex: confining molecules to molecular mechanisms. Trends Mol Med 2006;12:293-297. (Review). He W, Lu Y, Oahwash I, Hu XY, Chang A, Yan R. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med 2004;10:959-965. Shimakage M, Inoue N, Ohshima K, Kawahara K, Oka T, Yasui K, Matsumoto K, Inoue H, Watari A, Higashiyama S, Yutsudo M. Down-regulation of ASY/Nogo transcription associated with progression of adult T-cell leukemia/lymphoma. Int J Cancer 2006;119:1648-1653. Huang X, Yang H, Zhou Y, Liu J, Yin B, Peng X, Qiang B, Yuan J. Overexpression of human reticulon 3 (hRTN3) in astrocytoma. Clin Neuropathol 2004;23:1-7. Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A, Paloscia A, Spalletta G, Caltagirone C, Pizzuti A, Dallapiccola B. Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Human Mutat 2004;24:534-535. Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 2006;124:573-586. Yan R, Shi Q, Hu X, Zhou X. Reticulon proteins: emerging players in neurodegenerative diseases. Cell Mol Life Sci 2006;63:877-889. (Review). Rousseau S, Peggie M, Campbell DG, Nebreda AR, Cohen P. Nogo-B is a new physiological substrate for MAPKAP-K2. Biochem J 2005;391:433-440. This article should be referenced as such: Yutsudo M. RTN4 (reticulon 4). Atlas Genet Cytogenet Oncol Haematol.2007;11(2):128-130. Zheng B, Atwal J, Ho C, Case L, He XL, Garcia KC, Steward O, Tessier-Lavigne M. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote Atlas Genet Cytogenet Oncol Haematol. 2007;11(2) 130