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  1. Article: Editorial: RNA at a breaking point? Cytoplasmic cleavage and other post-transcriptional RNA processing in neurodevelopment and disease.

    Piwecka, Monika / Luisier, Raphaelle / Andreassi, Catia

    Frontiers in molecular neuroscience

    2023  Volume 16, Page(s) 1214853

    Language English
    Publishing date 2023-05-30
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2023.1214853
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The predicted RNA-binding protein regulome of axonal mRNAs.

    Luisier, Raphaëlle / Andreassi, Catia / Fournier, Lisa / Riccio, Antonella

    Genome research

    2023  Volume 33, Issue 9, Page(s) 1497–1512

    Abstract: Neurons are morphologically complex cells that rely on the compartmentalization of protein expression to develop and maintain their cytoarchitecture. The targeting of RNA transcripts to axons is one of the mechanisms that allows rapid local translation ... ...

    Abstract Neurons are morphologically complex cells that rely on the compartmentalization of protein expression to develop and maintain their cytoarchitecture. The targeting of RNA transcripts to axons is one of the mechanisms that allows rapid local translation of proteins in response to extracellular signals. 3' Untranslated regions (UTRs) of mRNA are noncoding sequences that play a critical role in determining transcript localization and translation by interacting with specific RNA-binding proteins (RBPs). However, how 3' UTRs contribute to mRNA metabolism and the nature of RBP complexes responsible for these functions remains elusive. We performed 3' end sequencing of RNA isolated from cell bodies and axons of sympathetic neurons exposed to either nerve growth factor (NGF) or neurotrophin 3 (NTF3, also known as NT-3). NGF and NTF3 are growth factors essential for sympathetic neuron development through distinct signaling mechanisms. Whereas NTF3 acts mostly locally, NGF signal is retrogradely transported from axons to cell bodies. We discovered that both NGF and NTF3 affect transcription and alternative polyadenylation in the nucleus and induce the localization of specific 3' UTR isoforms to axons, including short 3' UTR isoforms found exclusively in axons. The integration of our data with CLIP sequencing data supports a model whereby long 3' UTR isoforms associate with RBP complexes in the nucleus and, upon reaching the axons, are remodeled locally into shorter isoforms. Our findings shed new light into the complex relationship between nuclear polyadenylation, mRNA localization, and local 3' UTR remodeling in developing neurons.
    MeSH term(s) Nerve Growth Factor/genetics ; Nerve Growth Factor/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; 3' Untranslated Regions ; Axons/metabolism ; Protein Isoforms/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
    Chemical Substances Nerve Growth Factor (9061-61-4) ; RNA, Messenger ; 3' Untranslated Regions ; Protein Isoforms ; RNA-Binding Proteins
    Language English
    Publishing date 2023-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.277804.123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Image-based deep learning reveals the responses of human motor neurons to stress and VCP-related ALS.

    Verzat, Colombine / Harley, Jasmine / Patani, Rickie / Luisier, Raphaëlle

    Neuropathology and applied neurobiology

    2021  Volume 48, Issue 2, Page(s) e12770

    Abstract: Aims: Although morphological attributes of cells and their substructures are recognised readouts of physiological or pathophysiological states, these have been relatively understudied in amyotrophic lateral sclerosis (ALS) research.: Methods: In this ...

    Abstract Aims: Although morphological attributes of cells and their substructures are recognised readouts of physiological or pathophysiological states, these have been relatively understudied in amyotrophic lateral sclerosis (ALS) research.
    Methods: In this study, we integrate multichannel fluorescence high-content microscopy data with deep learning imaging methods to reveal-directly from unsegmented images-novel neurite-associated morphological perturbations associated with (ALS-causing) VCP-mutant human motor neurons (MNs).
    Results: Surprisingly, we reveal that previously unrecognised disease-relevant information is withheld in broadly used and often considered 'generic' biological markers of nuclei (DAPI) and neurons (
    Conclusions: Our study therefore reveals disease-relevant information contained in a range of both generic and more specific fluorescent markers and establishes the use of image-based deep learning methods for rapid, automated and unbiased identification of biological hypotheses.
    MeSH term(s) Amyotrophic Lateral Sclerosis/metabolism ; Deep Learning ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Neurites/metabolism ; Phenotype
    Language English
    Publishing date 2021-10-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80371-6
    ISSN 1365-2990 ; 0305-1846
    ISSN (online) 1365-2990
    ISSN 0305-1846
    DOI 10.1111/nan.12770
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  4. Article: Blimp-1 and c-Maf regulate

    Cox, Luke S / Alvarez-Martinez, Marisol / Wu, Xuemei / Gabryšová, Leona / Luisier, Raphaëlle / Briscoe, James / Luscombe, Nicholas M / O'Garra, Anne

    Wellcome open research

    2023  Volume 8, Page(s) 403

    Abstract: Background: CD4 : Methods: We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4 : Results: We show that the ... ...

    Abstract Background: CD4
    Methods: We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4
    Results: We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce
    Conclusions: These data show that Blimp-1 and c-Maf positively and negatively regulate a network of both unique and common anti-inflammatory and pro-inflammatory genes to reinforce a Th1 response in mice that will eradicate pathogens with minimum immunopathology.
    Language English
    Publishing date 2023-12-01
    Publishing country England
    Document type Journal Article
    ISSN 2398-502X
    ISSN 2398-502X
    DOI 10.12688/wellcomeopenres.19680.2
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  5. Article ; Online: Mammary epithelial morphogenesis in 3D combinatorial microenvironments.

    Luisier, Raphaelle / Girgin, Mehmet / Lutolf, Matthias P / Ranga, Adrian

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 21635

    Abstract: Human mammary epithelial cells can proliferate and reorganize into polarized multi-cellular constructs in-vitro, thereby functioning as an important model system in recapitulating key steps of in-vivo morphogenesis. Current approaches to constructing ... ...

    Abstract Human mammary epithelial cells can proliferate and reorganize into polarized multi-cellular constructs in-vitro, thereby functioning as an important model system in recapitulating key steps of in-vivo morphogenesis. Current approaches to constructing such three-dimensional mimics of the in-vivo microenvironment have involved the use of complex and ill-defined naturally derived matrices, whose properties are difficult to manipulate independently, and which have therefore limited our ability to understand the extrinsic regulation of morphogenesis. Here, we employ an automated, high-throughput approach to array modular building blocks of synthetic components, and develop a systematic approach to analyze colonies resulting from these varied microenvironmental combinations. This methodology allows us to systematically map the relationship between microenvironmental properties and ensuing morphogenetic phenotypes. Our analysis reveals that apico-basal polarity of mammary epithelial cells occurs within a narrow range of matrix stiffness, and that phenotypic homogeneity is favored in matrices which are insensitive to MMP-mediated degradation. Furthermore, combinations of extracellular proteins in the matrix finely tune the morphology of the mammary colonies, suggesting that subtle disregulations of the microenvironment may play a significant role in pathological disease states. This approach, which leverages the combinatorial possibilities of modular synthetic artificial extracellular matrices with an automated technology platform, demonstrates how morphogenesis can be assessed systematically in 3D, and provides new insights into mammary epithelial multicellularity.
    MeSH term(s) Cell Polarity ; Cell Proliferation ; Extracellular Matrix/metabolism ; Humans ; Mammary Glands, Human/cytology ; Mammary Glands, Human/metabolism ; Morphogenesis
    Language English
    Publishing date 2020-12-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-78432-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Physiological intron retaining transcripts in the cytoplasm abound during human motor neurogenesis.

    Petrić Howe, Marija / Crerar, Hamish / Neeves, Jacob / Harley, Jasmine / Tyzack, Giulia E / Klein, Pierre / Ramos, Andres / Patani, Rickie / Luisier, Raphaëlle

    Genome research

    2022  Volume 32, Issue 10, Page(s) 1808–1825

    Abstract: Intron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development; however, the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. Here we show ... ...

    Abstract Intron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development; however, the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. Here we show that IR is a physiological process that is spatiotemporally regulated during MN lineage restriction and that IRTs in the cytoplasm are detected in as many as 13% (
    MeSH term(s) Humans ; Introns ; Cytoplasm/genetics ; Cytoplasm/metabolism ; Motor Neurons ; Neurogenesis/genetics ; MicroRNAs/genetics ; MicroRNAs/metabolism
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2022-09-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.276898.122
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  7. Article ; Online: Paraspeckle components NONO and PSPC1 are not mislocalized from motor neuron nuclei in sporadic ALS.

    Tyzack, Giulia E / Manferrari, Giulia / Newcombe, Jia / Luscombe, Nicholas M / Luisier, Raphaelle / Patani, Rickie

    Brain : a journal of neurology

    2020  Volume 143, Issue 8, Page(s) e66

    MeSH term(s) Amyotrophic Lateral Sclerosis/metabolism ; Cell Nucleus/metabolism ; DNA-Binding Proteins/metabolism ; Female ; Humans ; Male ; Motor Neurons/metabolism ; RNA-Binding Proteins/metabolism
    Chemical Substances DNA-Binding Proteins ; NONO protein, human ; PSPC1 protein, human ; RNA-Binding Proteins
    Language English
    Publishing date 2020-08-25
    Publishing country England
    Document type Letter
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awaa205
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  8. Article ; Online: Aberrant cytoplasmic intron retention is a blueprint for RNA binding protein mislocalization in VCP-related amyotrophic lateral sclerosis.

    Tyzack, Giulia E / Neeves, Jacob / Crerar, Hamish / Klein, Pierre / Ziff, Oliver / Taha, Doaa M / Luisier, Raphaëlle / Luscombe, Nicholas M / Patani, Rickie

    Brain : a journal of neurology

    2021  Volume 144, Issue 7, Page(s) 1985–1993

    Abstract: We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However, the generalizability and potential roles of ... ...

    Abstract We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However, the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep sequencing of nuclear and cytoplasmic fractions of human induced pluripotent stem cells undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins. Remarkably, TDP-43, SFPQ and FUS-RNA binding proteins known for nuclear-to-cytoplasmic mislocalization in ALS-abundantly and specifically bind to this aberrant cytoplasmic pool of IRTs. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Cytoplasm/metabolism ; Humans ; Introns ; Mutation ; RNA-Binding Proteins/metabolism ; Valosin Containing Protein/genetics
    Chemical Substances RNA-Binding Proteins ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6)
    Language English
    Publishing date 2021-03-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awab078
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  9. Article ; Online: Automated and unbiased discrimination of ALS from control tissue at single cell resolution.

    Hagemann, Cathleen / Tyzack, Giulia E / Taha, Doaa M / Devine, Helen / Greensmith, Linda / Newcombe, Jia / Patani, Rickie / Serio, Andrea / Luisier, Raphaëlle

    Brain pathology (Zurich, Switzerland)

    2021  Volume 31, Issue 4, Page(s) e12937

    Abstract: Histopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell-to-cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and ...

    Abstract Histopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell-to-cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given disease attribute. Here, we tested different machine learning methods to analyse high-content microscopy measurements of hundreds of motor neurons (MNs) from amyotrophic lateral sclerosis (ALS) post-mortem tissue sections. Furthermore, we automated the identification of phenotypically distinct MN subpopulations in VCP- and SOD1-mutant transgenic mice, revealing common morphological cellular phenotypes. Additionally we established scoring metrics to rank cells and tissue samples for both disease probability and severity. By adapting this paradigm to human post-mortem tissue, we validated our core finding that morphological descriptors robustly discriminate ALS from control healthy tissue at single cell resolution. Determining disease presence, severity and unbiased phenotypes at single cell resolution might prove transformational in our understanding of ALS and neurodegeneration more broadly.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Animals ; Mice ; Mice, Transgenic ; Mitochondria/pathology ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Phenotype ; Spinal Cord/pathology ; Superoxide Dismutase/metabolism
    Chemical Substances Superoxide Dismutase (EC 1.15.1.1)
    Language English
    Publishing date 2021-02-11
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1051484-3
    ISSN 1750-3639 ; 1015-6305
    ISSN (online) 1750-3639
    ISSN 1015-6305
    DOI 10.1111/bpa.12937
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  10. Article ; Online: Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology.

    Ziff, Oliver J / Neeves, Jacob / Mitchell, Jamie / Tyzack, Giulia / Martinez-Ruiz, Carlos / Luisier, Raphaelle / Chakrabarti, Anob M / McGranahan, Nicholas / Litchfield, Kevin / Boulton, Simon J / Al-Chalabi, Ammar / Kelly, Gavin / Humphrey, Jack / Patani, Rickie

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 2176

    Abstract: Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced ... ...

    Abstract Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.
    MeSH term(s) Alternative Splicing/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Cadaver ; Cohort Studies ; Datasets as Topic ; DNA Damage ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/genetics ; Gene Fusion ; Genomic Instability ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/cytology ; Motor Neurons/metabolism ; Mutation ; Spinal Cord/metabolism ; Transcriptome/genetics ; Humans
    Chemical Substances C9orf72 protein, human ; DNA-Binding Proteins ; FUS protein, human ; SOD1 protein, human ; TARDBP protein, human ; TP53 protein, human
    Language English
    Publishing date 2023-04-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-37630-6
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