Alternative poly(A) site-selection regulates the production of alternatively spliced vesl-1/homer1 isoforms that encode postsynaptic scaffolding proteins.
The vesl-1/homer1 gene encodes a scaffold protein that interacts with several receptors to modulate synaptic functions. The gene also encodes two shorter forms that counteract the functions of the long form of Vesl. Expression of the shorter forms is driven by neural activities such as long-term potentiation. Here we analyzed the mechanism regulating vesl-1 alternative splicing. Each functional poly(A) site was in a different part of the 3'-terminal exon, with promoter-proximal and promoter-distal sites at the end of exons corresponding to the short and long form Vesl-1, respectively. 3'-End-processing at proximal poly(A) site, specifically at the vesl-1M poly(A) site, was enhanced by extracellular stimuli, thereby switching transcription termination from promoter-distal to -proximal poly(A) site. This switch was not specifically coupled to the vesl-1 promoter and was independent of de novo protein synthesis. Analysis of transcripts from mini-genes that mimic the structure of endogenous vesl-1 revealed that the vesl-1M poly(A) region plays a crucial role in switching to the alternative pre-mRNA splicing that is triggered by extracellular stimuli. Therefore, a 3'-end-processing event regulates the neural activity-dependent alternative splicing of vesl-1. This is the first report of a gene in which alternative poly(A) site-selection regulates alternative splicing in a protein synthesis-independent manner.
Niibori
Yosuke
Y
Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya, Machida, Tokyo, Japan.
Hayashi
Fumihiko
F
Hirai
Keiko
K
Matsui
Minoru
M
Inokuchi
Kaoru
K
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002490:Central Nervous System / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D000072233:Homer Scaffolding Proteins; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D026723:Polyadenylation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics*; D051381:Rats; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; C000606624:Homer1 protein, rat; D020033:Protein Isoforms; D022821:RNA Splice Sites