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Complex post-transcriptional regulation of Pumilio 2 fine-tunes the neuron
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Highly polarized cells, such as differentiated

neurons, requires a sophisticated network of

regulatory events to control gene expression

in response to different environmental as

well as developmental conditions. In this

study we show how different RNA processing

events can work in concert to regulate gene

expression of Pumillio 2 (Pum2), a

translational repressor important for

neuronal homeostasis as well as memory and

learning. We have previously shown that

miRNAs, encoded within the miR379-410

cluster, which regulate the Pum2 expression

in turn are regulated by A-to-I editing. Here,

we identify an alternative splicing event

within the Pum2 3’UTR that facilitates the

escape of targeting by many of these

miRNAs. We propose that splicing and

editing are two RNA processing events that

can work in concert to fine-tune the

expression of Pum2 and have different

effects depending on the neuronal

subcellular localization of the transcript.

This enables a differential gene expression in

different compartments of the cell such as

cell body and synaptic buds.

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-93321OAI: oai:DiVA.org:su-93321DiVA: diva2:646226
Available from: 2013-09-06 Created: 2013-09-06 Last updated: 2013-09-10
In thesis
1. A-to-I RNA editing: Function and consequences during brain development
Open this publication in new window or tab >>A-to-I RNA editing: Function and consequences during brain development
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of my thesis has been to study how A-to-I RNA editing of miRNAs is regulated during brain development and the biological function of these editing events.

Using high throughput RNA sequencing, we performed an unbiased search for edited, mature miRNAs in total mouse brain tissue from three developmental stages. We searched for known and novel editing sites within short RNA sequences approximately resembling the length of mature miRNAs.

We can conclude that the gradual increase in editing efficiency seen for most selectively edited sites in transcripts encoding neurotransmission proteins, also applies to miRNAs during development of the mammalian brain. The most striking editing events all occur in the crucial seed sequence, essential for target recognition. These results indicate that A-to-I editing is utilized to diversify target recognition by the miRNAs during development.

Furthermore, our data suggests that specific transcripts, targeted by either non-edited or edited miRNAs, are regulated in a manner that is consistent with the developmental shifts in editing frequencies. One example of this is the developmentally regulated editing of miR-381, targeting the Pum2 transcript in the brain. Pum2 is a translational repressor that regulates many mRNAs shown to be important for neurological functions, including memory formation and learning.

We have further analyzed what determines a substrate to be edited by the ADAR enzymes, specifically in the context of the mammalian GABAA receptor. We found that long stem loop structures located close to exon sequences function as inducers of exonic editing.

Taken together, my research demonstrate the power of combining, RNA-Seq, bioinformatics and specific experimental verifications in order to shed light on the impact of A-to-I editing on the process of RNA interference. Furthermore, we have expanded the knowledge of RNA structure requirements for ADAR editing to occur. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 54 p.
Keyword
RNA editing, miRNAs, Brain development
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-93137 (URN)978-91-7447-739-9 (ISBN)
Public defence
2013-10-11, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper 3: Manuscript

Available from: 2013-09-19 Created: 2013-09-03 Last updated: 2013-09-10Bibliographically approved

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