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NEURO_NMD SIGNED

Functional impact of alternative splicing coupled to nonsense-mediated decay in developing neurons

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 NEURO_NMD project word cloud

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significance    global    transcriptional    rna    stages    time    unclear    gene    splicing    insights    post    elucidate    first    expression    precise    fashion    repertoire    inhibiting    decay    network    questions    nonsense    earlier    exons    mature    alternative    sequencing    mechanisms    nmd    poorly    seq    transcriptome    systematically    inactivation    stem    orchestrate    neuronal    precursor    embryonic    neurons    uncover    regulation    separate    inclusion    appropriate    actin    cell    manner    quantitative    developmental    mechanism    considerable    functions    cytoskeleton    dynamics    neural    coupled    biological    oligonucleotides    cells    acutely    encoding    brain    functional    regulator    antisense    resolved    mediated    contributes    undergoes    differentiation    genetic    contexts    spatiotemporal    underlying    morphological    ptbp1    primary    attain    undergoing    relies    genes    corresponding    mouse    coordinated    modulating    critical    fit    mrna   

Project "NEURO_NMD" data sheet

The following table provides information about the project.

Coordinator
KING'S COLLEGE LONDON 

Organization address
address: STRAND
city: LONDON
postcode: WC2R 2LS
website: www.kcl.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2016
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2017
 Duration (year-month-day) from 2017-05-01   to  2019-12-04

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KING'S COLLEGE LONDON UK (LONDON) coordinator 183˙454.00

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 Project objective

Differentiation of precursor cells into mature neurons relies on transcriptome-wide changes in gene expression that have to be coordinated in a precise spatiotemporal fashion. Alternative pre-mRNA splicing coupled to nonsense-mediated decay (AS-NMD) is a widespread post-transcriptional mechanism known to orchestrate gene expression dynamics in developmental contexts. Earlier studies identified several neural targets of this pathway; however, in most cases, the extent to which AS-NMD contributes to the overall gene expression dynamics and biological significance of this regulation is poorly understood. Moreover, whether AS-NMD target repertoire undergoes considerable changes in developing brain and how this might fit to the global regulation network underlying neuronal differentiation remains unclear. I will address these questions using two separate approaches. First, I will investigate novel AS-NMD targets encoding actin cytoskeleton factors and controlled by an important regulator of neuronal alternative splicing, Ptbp1. I will elucidate the extent of AS-NMD regulation in these genes by modulating the inclusion of the NMD-promoting exons with corresponding antisense oligonucleotides. in mouse embryonic stem cells undergoing neuronal differentiation, neural stem cells and primary neurons. Second, I will systematically analyse how NMD contributes to different stages of neuronal development by acutely inhibiting this pathway in a time-resolved manner using genetic means. I will then identify gene expression effects and functional consequences of NMD inactivation using transcriptome sequencing (RNA-Seq) and appropriate cell biological methods. All in all, this work will provide critical quantitative insights into AS-NMD functions and uncover novel mechanisms allowing neurons to attain their unique morphological and functional properties.

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