Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

RTN4 ( 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; Identity RTN4-A; RTN4-B1; RTN4-B2; RTN4-C Hugo: RTN4 Location: 2p16.3 Other names: ASY; NI220/250; NOGO; NOGO-A; Local order: Between FLJ42562 and FLJ31438.

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 spans about 75kb, and contains 9 Note: Down-regulation of RTN4 expression was major exons and several different cap sites (Fig. 2a). observed in small cell lung carcinomas and adult T-cell Transcription leukemia/lymphomas, and RTN3, one of RTN4 interacting , was over-expressed in Three major, RTN4-A, B1 and C, (Fig. 2b) and several astrocytomas, suggesting involvement of RTN4 (and minor transcriptional isoforms result from alternative RTN3) in certain types of tumorigenesis. However, splicing and/or differential promoter usage. Although increased incidence of tumor formation has not been RTN4 mRNA is ubiquitously expressed, the expression observed in RTN4 knock out mice. of isoforms is tissue-specific, for example, RTN4-A RTN4 is also suspected to involve in schizophrenia and and C in brain, RTN4-C in muscle, and RTN4-B1 in neuronal degenerative diseases. many other tissues. References Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Description Spillmann AA, Christ F, Schwab ME. Nogo-A is a myelin- associated neurite outgrowth inhibitor and an antigen for Proteins with different sizes are synthesized from monoclonal antibody IN-1. Nature 2000;403:434-439. different mRNA isoforms: RTN4-A, 129.9 kDa (1192 GrandPré T, Nakamura F, Vartanian T, Strittmatter SM. amino acids); RTN4-B1, 40.3 kDa (373 amino acids); Identification of the Nogo inhibitor of regeneration as a RTN4-B2, 42.3 kDa (392 amino acids); RTN4-C, 22.4 Reticulon protein. Nature 2000;403:439-444. kDa (199 amino acids). All RTN4 protein isoforms Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie retain a common C-terminal domain containing two G, Michalovich D, Simmons DL, Walsh FS. Inhibitor of neurite outgrowth in humans. Nature 2000;403:383-384. trans-membrane domains and an endoplasmic Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y. A reticulum (ER)-retrieval motif. novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity. Expression Oncogene 2000;19:5736-5746. Ubiquitously expressed (see Transcription). Yang J, Yu L, Bi AD, Zhao SY. Assignment of the human reticulon 4 gene (RTN4) to 2p14---2p13 by Localisation radiation hybrid mapping. Cytogenet Cell Genet 2000;88:101- RTN4 protein localizes predominantly in the ER and, 102. to a lesser extent, in cytoplasmic membrane. Fournier AE, GrandPré T, Strittmatter SM. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Function Nature 2001;409:341-346. Although definitive functional mechanisms of RTN4 Li Q, Qi B, Oka K, Shimakage M, Yoshioka N, Inoue H, Hakura have not yet been clarified, RTN4 protein interacts with A, Kodama K, Stanbridge EJ, Yutsudo M. Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer. several other proteins, including RTN1, RTN3, Oncogene 2001;20:3929-3936. DP1/Yop1p, BACE1, and Nogo receptor (NogoR). Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de Interaction with DP1/Yop1p, an ER membrane protein, Tapia M, Pradat PF, Lacomblez L, Seihlan D, Prinjha R, Walsh may be necessary for maintenance or stabilization of FS, Meininger V, Loeffler JP. Nogo provides a molecular tubular ER. Binding with BACE1 (beta-amyloid marker for diagnosis of amyotrophic lateral sclerosis. Neurobiol converting enzyme 1) results in reduction in BACE1 Dis 2002;10:358-365. Novak G, Kim D, Seemen P, Tallerico T. Schizophrenia and activity and production of amyloid-beta. RTN4 also Nogo: elevated mRNA in cortex, and high prevalence of a interacts with NogoR, and may lead to activation of homozygous CAA insert. Brain Res Mol Brain Res RhoA and inhibition of neuronal regeneration in central 2002;107:183-189. nervous system. Further, overexpression of RTN4 may Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM. Axon cause ER stress and apoptosis in certain cells. 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 Four reticulon family members (RTN1, RTN2, RTN3 structure and functional characterization of the promoters of and RTN4) have been identified. They possess a highly human and mouse nogo/rtn4. J Mol Biol 2003;325:299-323. conserved C-terminal domain named reticulon Oertle T, Schwab ME. Nogo and its partners. Trends Cell Biol 2003;13:187-194. (Review). homology domain.

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Qi B, Qi Y, Watari A, Yoshioka N, Inoue H, Minemoto Y, corticospinal tract regeneration in vivo. Proc Natl Acad Sci Yamashita K, Sasagawa T, Yutsudo M. Pro-apoptotic USA 2005;102:1205-1210. ASY/Nogo-B protein associates with ASYIP. J Cell Physiol Chen Y, Tang X, Cao X, Chen H, Zhang X. Human Nogo-C 2003;196:312-318. overexpression induces HEK293 cell apoptosis via a Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, mechanism that involves JNK-c-Jun pathway. Biochem Ledermann B, Christ F, Sansig G, van der Putten H, Schwab Biophys Res Commun 2006;348:923-928. ME. Systemic deletion of the myelin-associated outgrowth Kuang E, Wan Q, Li X, Zou T, Qi Y. ER stress triggers inhibitor Nogo-A improves regenerative and plastic responses apoptosis induced by Nogo-B/ASY overexpression. Exp Cell after . Neuron 2003;38:201-211. Res 2006;312:1983-1988. Watari A, Yutsudo M. Multi-functional gene ASY/Nogo/RTN- Murayama KS, Kametani F, Saito S, Kume H, Akiyama H, X/RTN4: Apoptosis, tumor suppression, and inhibition of Araki W. RTN3 and RTN4-B/C interact with BACE1 neuronal regeneration. Apoptosis 2003;8:5-9. (Review). and inhibit its ability to produce amyloid beta-protein. Eur J Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne Neurosci 2006;24:1237-1244. M. Lack of enhanced spinal regeneration in Nogo-deficient Novak G, Tallerico T. Nogo A, B and C expression in mice. Neuron 2003;38:213-224. schizophrenia, depression and bipolar cortex, and correlation Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, of Nogo expression with CAA/TATC polymorphism in 3-UTR. Fulton D, Tempst P, Strittmatter SM, Sessa WC. A new role for Brain Res 2006;1120:161-171. Nogo as a regulator of vascular remodeling. Nat Med Schwab JM, Tuli SK, Failli V. The Nogo receptor complex: 2004;10:382-388. confining molecules to molecular mechanisms. Trends Mol He W, Lu Y, Oahwash I, Hu XY, Chang A, Yan R. Reticulon Med 2006;12:293-297. (Review). family members modulate BACE1 activity and amyloid-beta Shimakage M, Inoue N, Ohshima K, Kawahara K, Oka T, peptide generation. Nat Med 2004;10:959-965. Yasui K, Matsumoto K, Inoue H, Watari A, Higashiyama S, Huang X, Yang H, Zhou Y, Liu J, Yin B, Peng X, Qiang B, Yutsudo M. Down-regulation of ASY/Nogo transcription Yuan J. Overexpression of human reticulon 3 (hRTN3) in associated with progression of adult T-cell astrocytoma. Clin Neuropathol 2004;23:1-7. leukemia/lymphoma. Int J Cancer 2006;119:1648-1653. Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A, Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. A Paloscia A, Spalletta G, Caltagirone C, Pizzuti A, Dallapiccola class of membrane proteins shaping the tubular endoplasmic B. Mutations of the Nogo-66 receptor (RTN4R) gene in reticulum. Cell 2006;124:573-586. schizophrenia. Human Mutat 2004;24:534-535. Yan R, Shi Q, Hu X, Zhou X. Reticulon proteins: emerging Rousseau S, Peggie M, Campbell DG, Nebreda AR, Cohen P. players in neurodegenerative diseases. Cell Mol Life Sci Nogo-B is a new physiological substrate for MAPKAP-K2. 2006;63:877-889. (Review). Biochem J 2005;391:433-440. Zheng B, Atwal J, Ho C, Case L, He XL, Garcia KC, Steward This article should be referenced as such: O, Tessier-Lavigne M. Genetic deletion of the Nogo receptor Yutsudo M. RTN4 (reticulon 4). Atlas Genet Cytogenet Oncol does not reduce neurite inhibition in vitro or promote Haematol.2007;11(2):128-130.

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