Dataset Information

Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil.

ABSTRACT: The stability and dynamics of synapses rely on tight regulation of the synaptic proteome. Shank proteins, encoded by the three genes Shank1, Shank2 and Shank3 are scaffold molecules in the postsynaptic density of excitatory neurons that contribute to activity-dependent neuronal signalling. Mutations in the Shank genes are associated with neurological diseases. Using state-of-the-art technologies, we investigated the levels of expression of the Shank family messenger RNAs (mRNAs) within the synaptic neuropil of the rat hippocampus. We detected all three Shank transcripts in the neuropil of CA1 pyramidal neurons. We found Shank1 to be the most abundantly expressed among the three Shank mRNA homologues. We also examined the turnover of Shank mRNAs and predict the half-lives of Shank1, Shank2 and Shank3 mRNAs to be 18-28 h. Using 3'-end sequencing, we identified novel 3' ends for the Shank1 and Shank2 3' untranslated regions (3' UTRs) that may contribute to the diversity of alternative polyadenylation (APA) for the Shank transcripts. Our findings consolidate the view that the Shank molecules play a central role at the postsynaptic density. This study may shed light on synaptopathologies associated with disruption of local protein synthesis, perhaps linked to mutations in mRNA 3' UTRs or inappropriate 3' end processing.

SUBMITTER: Epstein I

PROVIDER: S-EPMC3843870 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil.

Epstein Irina I Tushev Georgi G Will Tristan J TJ Vlatkovic Irena I Cajigas Iván J IJ Schuman Erin M EM

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20131202 1633

The stability and dynamics of synapses rely on tight regulation of the synaptic proteome. Shank proteins, encoded by the three genes Shank1, Shank2 and Shank3 are scaffold molecules in the postsynaptic density of excitatory neurons that contribute to activity-dependent neuronal signalling. Mutations in the Shank genes are associated with neurological diseases. Using state-of-the-art technologies, we investigated the levels of expression of the Shank family messenger RNAs (mRNAs) within the synap ...[more]

PMID: 24298140

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Project description:BACKGROUND:Odorant receptor genes constitute the largest gene family in mammalian genomes and this family has been extensively studied in several species, but to date far less attention has been paid to the characterization of their mRNA 3' untranslated regions (3'UTRs). Given the increasing importance of UTRs in the understanding of RNA metabolism, and the growing interest in alternative polyadenylation especially in the nervous system, we aimed at identifying the alternative isoforms of odorant receptor mRNAs generated through 3'UTR variation. RESULTS:We implemented a dedicated pipeline using IsoSCM instead of Cufflinks to analyze RNA-Seq data from whole olfactory mucosa of adult mice and obtained an extensive description of the 3'UTR isoforms of odorant receptor mRNAs. To validate our bioinformatics approach, we exhaustively analyzed the 3'UTR isoforms produced from 2 pilot genes, using molecular approaches including northern blot and RNA ligation mediated polyadenylation test. Comparison between datasets further validated the pipeline and confirmed the alternative polyadenylation patterns of odorant receptors. Qualitative and quantitative analyses of the annotated 3' regions demonstrate that 1) Odorant receptor 3'UTRs are longer than previously described in the literature; 2) More than 77% of odorant receptor mRNAs are subject to alternative polyadenylation, hence generating at least 2 detectable 3'UTR isoforms; 3) Splicing events in 3'UTRs are restricted to a limited subset of odorant receptor genes; and 4) Comparison between male and female data shows no sex-specific differences in odorant receptor 3'UTR isoforms. CONCLUSIONS:We demonstrated for the first time that odorant receptor genes are extensively subject to alternative polyadenylation. This ground-breaking change to the landscape of 3'UTR isoforms of Olfr mRNAs opens new avenues for investigating their respective functions, especially during the differentiation of olfactory sensory neurons.

Project description:Alternative transcription is common in eukaryotic cells and plays important role in regulation of cellular processes. Alternative polyadenylation results from ambiguous PolyA signals in 3' untranslated region (UTR) of a gene. Such alternative transcripts share the same coding part, but differ by a stretch of UTR that may contain important functional sites.The methodoogy of this study is based on mathematical modeling, analytical solution, and subsequent validation by datamining in multiple independent experimental data from previously published studies.In this study we propose a mathematical model that describes the population dynamics of alternatively polyadenylated transcripts in conjunction with rhythmic expression such as transcription oscillation driven by circadian or metabolic oscillators. Analysis of the model shows that alternative transcripts with different turnover rates acquire a phase shift if the transcript decay rate is different. Difference in decay rate is one of the consequences of alternative polyadenylation. Phase shift can reach values equal to half the period of oscillation, which makes alternative transcripts oscillate in abundance in counter-phase to each other. Since counter-phased transcripts share the coding part, the rate of translation becomes constant. We have analyzed a few data sets collected in circadian timeline for the occurrence of transcript behavior that fits the mathematical model.Alternative transcripts with different turnover rate create the effect of rectifier. This "molecular diode" moderates or completely eliminates oscillation of individual transcripts and stabilizes overall protein production rate. In our observation this phenomenon is very common in different tissues in plants, mice, and humans. The occurrence of counter-phased alternative transcripts is also tissue-specific and affects functions of multiple biological pathways. Accounting for this mechanism is important for understanding the natural and engineering the synthetic cellular circuits.

Dataset Information

Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil.

Publications

Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil.

Similar Datasets

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