Tissue specificity and regulation of the N-terminal diversity of reticulon 3.
Over the last few years, the widely distributed family of reticulons (RTNs) is receiving renewed interest because of the implication of RTN4/Nogo in neurite regeneration. Four genes were identified in mammals and are referred to as RTN1, 2, 3 and the neurite outgrowth inhibitor RTN4/Nogo. In the present paper, we describe the existence of five new isoforms of RTN3 that differ in their N-termini, and analysed their tissue distribution and expression in neurons. We redefined the structure of human and murine rtn3 genes, and identified two supplementary exons that may generate up to seven putative isoforms arising by alternative splicing or differential promoter usage. We confirmed the presence of five of these isoforms at the mRNA and protein levels, and showed their preferential expression in the central nervous system. We analysed rtn3 expression in the cerebellum further, and observed increased levels of several of the RTN3 isoforms during cerebellum development and during in vitro maturation of cerebellar granule cells. This pattern of expression paralleled that shown by RTN4/Nogo isoforms. Specifically, RTN3A1 expression was down-regulated upon cell death of cerebellar granule neurons triggered by potassium deprivation. Altogether, our results demonstrate that the rtn3 gene generates multiple isoforms varying in their N-termini, and that their expression is tightly regulated in neurons. These findings suggest that RTN3 isoforms may contribute, by as yet unknown mechanisms, to neuronal survival and plasticity.
Di Scala
Franck
F
Laboratoire de Signalisations Moléculaires et Neurodégénérescence, EA 3433, Université Louis Pasteur, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France.
Dupuis
Luc
L
Gaiddon
Christian
C
De Tapia
Marc
M
Jokic
Natasa
N
Gonzalez de Aguilar
Jose-Luis
JL
Raul
Jean-Sébastien
JS
Ludes
Bertrand
B
Loeffler
Jean-Philippe
JP
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003001:Cloning, Molecular; D019295:Computational Biology; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D000070798:Nogo Proteins; D009928:Organ Specificity; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D008565:Membrane Proteins; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D012333:RNA, Messenger; C476198:RTN3 protein, human; C000603199:RTN4 protein, human; C482720:Rtn3 protein, mouse; C000603201:Rtn4 protein, mouse