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Stimulation-specific remodeling of the neuronal transcriptome via intron retention programs

Mazille, Maxime. Stimulation-specific remodeling of the neuronal transcriptome via intron retention programs. 2021, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/87423/

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Abstract

The mammalian brain's ability to constantly integrate, sort, and respond to a plethora of environmental changes is particularly impressive. This adaptability is called plasticity and supports brain functions such as learning, acquisition of skills, or memory formation. Transcription of distinct sets of pre-mRNA upon specific neuronal stimuli is critical for appropriate plasticity event formation. Besides transcription, a growing body of studies supports that nuclear sequestration of transcripts plays a critical role in shaping activity-dependent gene expression programs. Recent studies have revealed the existence of stable intron-retaining transcripts sequestered in the nucleus where they cannot participate in protein synthesis. Importantly, certain stable intron-retaining transcripts can complete their splicing and join the cytoplasm upon various types of cellular signals, including neuronal activity. However, this mechanism was only shown for a couple of candidate transcripts. Thus, it is unknown whether nuclear sequestration and cytosolic release of stable intron-retaining transcripts is a general mechanism allowing global neuronal transcriptome remodeling. Moreover, the studies reporting stimulus-dependent regulation of these intron-retaining transcripts were performed in different cellular models or focusing on individual transcripts. Thereby, it is unclear whether stable and nuclear intron-retaining transcripts can be regulated in a stimulus-specific manner.
In my thesis, I investigated whether nuclear sequestration of stable intron-retaining transcripts is a general mechanism and whether these transcripts can be regulated in a neuronal stimulus-specific manner. First, we found that most stable intron-retaining transcripts are sequestered in the nucleus. Then we probed the response of these nuclear transcripts upon elevation of neuronal network activity or treatment with BDNF, a neurotrophin. We show that stable and nuclear intron-retaining transcripts can complete their splicing upon these two neuronal stimuli and undergo cytoplasmic export. Interestingly, we also identify activity-dependent retained isoform decrease corresponding most likely to nuclear degradation. Importantly, we show for the first time that elevation of network activity and BDNF treatment control stimulation-specific populations of stable intron-retaining transcripts. Finally, stimulation specificity of these populations arises from molecularly distinct signaling pathways. Thereby, my thesis supports cue-specific remodeling of the neuronal transcriptome via splicing completion and cytoplasmic export of pre-existing intron-retaining transcripts. As it does not rely on de novo transcription, this mechanism can support rapid mobilization of new mRNAs upon distinct environmental changes and we speculate that it can support different forms of plasticity.
Advisors:Mauger, Oriane and Scheiffele, Peter and Doetsch, Fiona and M├╝hlemann , Oliver
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Cell Biology (Mauger)
UniBasel Contributors:Mauger, Oriane and Scheiffele, Peter and Doetsch, Fiona
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14595
Thesis status:Complete
Number of Pages:140
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss145953
edoc DOI:
Last Modified:01 Jan 2024 02:30
Deposited On:08 Feb 2022 11:32

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