Trends in Cell Biology
Nogo and its paRTNers
Section snippets
Taxonomic distribution and evolution of the RTN family
Genes for RTN-like proteins have been identified in most eukaryotic taxa and have evolved from an intron-rich ancestor (T. Oertle, unpublished). In prokaryotes, no homologues have been identified so far, suggesting that RTNs emerged relatively recently in eukaryotes, potentially in parallel with the evolution of the endomembrane system (T. Oertle, unpublished). There are four mammalian reticulon genes (RTN1, RTN2, RTN3 and Nogo/RTN4), each of which can give rise to a range of alternative
Tissue expression of mammalian RTN genes
The four mammalian RTN genes have a broad tissue expression pattern (Table 1) Most transcripts are enriched in nervous tissues (RTN1-A, RTN1-C, RTN2-A, RTN2-B, Nogo-A/RTN4-A). The RTN1 transcripts are almost exclusively expressed in neurons and neuroendocrine cells. Nogo-A/RTN4-A is expressed by oligodendrocytes, the myelin-forming cells of the adult CNS, and some neuronal subpopulations, heart and testis (Table 1). Two RTN transcripts (RTN2-C, Nogo-C/RTN4-C) are particularly enriched in
Subcellular localization
The shared feature of RTN proteins is their association with membranes of the endoplasmic reticulum (ER) [3] (Fig. 2b). This has been shown for mammalian RTN1 3, 15, RTN3 [16] and Nogo/RTN4 (4, 6; T. Oertle, unpublished) as well as for Drosophila Rtnl1 [17] and Caenorhabditis RTNL [18]. Because all RTNs lack a canonical leader peptide at their N-termini, translocation into the ER is assumed to be directed by internal signals (e.g. transmembrane domains). Alternatively, the ER association could
Membrane topology
The membrane topology of RTNs is of specific interest, particularly because the two very large (∼35 amino acid) putative transmembrane domains could both span the membrane either once or twice (Fig. 2). Immunofluorescence studies have shown that, in the prevalent ER-associated topology, the N- and C-termini of RTNs face the cytoplasm (6, 16; M. van der Haar, unpublished) (Fig. 2a). The 66-amino-acid loop between the two hydrophobic domains of Nogo-A cannot be detected by antibodies without
RTNs as marker proteins and their roles in neuronal differentiation
RTN1-A and RTN1-C are both expressed in most neuroendocrine tumours, such as SCLCs, whereas they are absent in atypical carcinoids 25, 26, 27. Only non-SCLCs showing a neuroendocrine immunophenotype also produce RTN1-A [28]. Thus, RTN1 is considered to be a highly sensitive and specific marker of neuroendocrine differentiation in lung cancer to be used in the diagnosis of this disease. Although it has been speculated that the presence of neuroendocrine markers could help to identify patients
ER function, plasma-membrane formation and cell division
Because RTNs are found in almost all eukaryotic cells and organisms, they would be expected to exert basic functions in the cellular machinery. Single RTN genes seem not to be of vital importance, however, because organisms with RTN gene disruptions (Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans and Drosophila melanogaster) are viable (e.g. 17, 18, 40). On the basis of the (few) existing data, the following hypotheses for cellular functions of RTN proteins can be
Concluding remarks
Research in the field of RTNs has increasingly moved beyond descriptive studies of their expression patterns and genomic structures towards functional enquiries. The role of Nogo in neurite-outgrowth inhibition is currently being studied extensively. By contrast, the roles of RTN1, RTN2 and RTN3 in vertebrates, the possible intracellular role of Nogo/RTN4, and the function of the RTN genes in invertebrates, plants and yeast are poorly understood, and represent an exciting subject for future
Acknowledgements
We thank O. Gilliéron and D. Merkler for providing unpublished data to complete Table 1, M. van der Haar for providing Fig. 2c, and A. Buss, D. Merkler, M. Kerschensteiner and S. DeMarco for critically reading the manuscript. We also thank E. Hochreutener and R. Schöb for excellent graphical work. Our own studies were supported by the Swiss National Science Foundation (grant 31-63633) and by the NCCR on Neural Plasticity and Repair.
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