Rosa Pascual

Walter and Eliza Hall Institute of Medical Research

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Raúl Méndez

Institute for Research in Biomedicine

Alba Millanes‐Romero

Institute for Research in Biomedicine

Oscar Reina

Institute for Research in Biomedicine

Gonzalo Fernández‐Miranda

Institute for Research in Biomedicine

Mihai G. Netea

Radboud University Nijmegen

Elliot Surgenor

Walter and Eliza Hall Institute of Medical Research

Nicolás Bellora

Consejo Nacional de Investigaciones Científicas y Técnicas

Esther Seco

Instituto de Investigación Sanitaria de Santiago

Wolfgang Huber

European Molecular Biology Laboratory

Eulàlia Belloc

Institute for Research in Biomedicine

Cooperative Institutions

Walter and Eliza Hall Institute of Medical Research

University of Melbourne

Institute for Research in Biomedicine

Spanish National Cancer Research Centre

University Medical Center

Radboud University Nijmegen

Radboud Institute for Molecular Life Sciences

Radboud University Medical Center

Heidelberg University

Centro de Investigación Biomédica en Red

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Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers

Nature Cell Biology (2024)

Rachel Joyce Rosa Pascual Luuk Heitink Bianca D. Capaldo François Vaillant

BRCA2 Protein

Proteostasis

10.1038/s41556-023-01315-5

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Cpeb2 in mammary gland homeòstasis and breast cancer

Rosa Pascual

espanolLa glandula mamaria es el unico organo que se desarrolla principalmente despues del nacimiento y, ademas, se remodela durante cada ciclo menstrual y embarazo a traves de expansiones e involuciones muy dinamicas del epitelio polarizado que la constituye. Por lo tanto, la glandula mamaria requiere un equilibrio finamente regulado entre proliferacion y diferenciacion. Este equilibro se encuentra perturbado en casos de cancer de mama. De que manera el control tradicional contribuye a la homeostasis y tumorigenesis de la glandula mamaria es un terreno por explorar. La familia de proteinas CPEBs (Cytoplasmic Polyadenylation Element Binding) incluye cuatro proteinas de union al RNA mensajero que regulan, de manera temporal y espacial, la traduccion y la localizacion sub-celular de los mRNAs que unen. Las CPEBs podrian regular hasta el 25% del genoma. Aqui presentamos un estudio sistematico de los cuatro miembro de la familia de las CPEBs (CPEB1-4) en el contexto de la glandula mamaria adulta, utilizando modelos knock-out (KO) en raton. Durante esta investigacion hemos descubierto que la falta de CPEB2 resulta en defectos en las ramificaciones de la glandula mamaria, y tambien en diferenciacion. De manera muy relevante, la deplecion de CPEB2 tiene consecuencias en cancer de mama. En conclusion, es trabajo descifra un nuevo mecanismo a nivel de traduccion responsable de la regulacion de la homeostasis y el desarrollo de tumores en la glandula mamaria. EnglishAbstract of the thesis “ CPEB2 in mammary gland homeostasis and breast cancer” PhD candidate: Rosa Pascual Domingo Facultad de Farmacia, Universitat de Barcelona The mammary gland develops postnatally and is remodeled, during each estrous cycle and pregnancy, through very dynamic expansions and involutions of the polarized epithelial tree. Thus, the mammary gland requires fine-regulated balance between proliferation and differentiation, which is disrupted in breast tumors. How translational control contributes to mammary gland homeostasis and tumorigenesis remain largely unexplored. The CPEB-family (Cytoplasmic Polyadenylation Element Binding) of RNA-binding proteins regulates, temporarily and spatially, the translation and subcellular localization of CPEB-bound mRNAs, accounting for up to 25% of the genome. Here we present a systematic study of the four members of the CPEB family (CPEB1-4) in the context of the adult mammary gland, using knock-out (KO) models for all four CPEBs. We discovered that the lack of CPEB2 results in defects in mammary gland branching and lineage specification. Interestingly, CPEB2 depletion also has consequences for breast tumorigenesis. Moreover, were able to identify the target mRNAs bound by CPEB2 in mammary epithelial cells and to establish a molecular mechanism by which CPEB2 regulates mammary gland homeostasis and breast cancer Altogether, this work unravels a novel translational mechanism regulating cell fate in the mammary gland and breast tumor development.

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Single cell 3’UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Manuel Göpferich Nikhil Oommen George Ana Domingo-Muelas Alex Bizyn Rosa Pascual

SUMMARY Autism spectrum disorder (ASD) is a neurodevelopmental disease affecting social behavior. Many of the high-confident ASD risk genes relate to mRNA translation. Specifically, many of these genes are involved in regulation of gene expression for subcellular compartmentalization of proteins 1 . Cis-regulatory motifs that often localize to 3’- and 5’-untranslated regions (UTRs) offer an additional path for posttranscriptional control of gene expression. Alternative cleavage and polyadenylation (APA) affect 3’UTR length thereby influencing the presence or absence of regulatory elements. However, APA has not yet been addressed in the context of neurodevelopmental disorders. Here we used single cell 3’end sequencing to examine changes in 3’UTRs along the differentiation from neural stem cells (NSCs) to neuroblasts within the adult brain. We identified many APA events in genes involved in neurodevelopment, many of them being high confidence ASD risk genes. Further, analysis of 3’UTR lengths in single cells from ASD and healthy individuals detected longer 3’UTRs in ASD patients. Motif analysis of modulated 3’UTRs in the mouse adult neurogenic lineage and ASD-patients revealed enrichment of the cytoplasmic and polyadenylation element (CPE). This motif is bound by CPE binding protein 4 (CPEB4). In human and mouse data sets we observed co-regulation of CPEB4 and the CPEB-binding synaptic adhesion molecule amyloid beta precursor-like protein 1 (APLP1). We show that mice deficient in APLP1 show aberrant regulation of APA, decreased number of neural stem cells, and autistic-like traits. Our findings indicate that APA is used for control of gene expression along neuronal differentiation and is altered in ASD patients.

Neuroblast

10.1101/2020.08.12.247627

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mRNA spindle localization and mitotic translational regulation by CPEB1 and CPEB4

RNA (2020)

Rosa Pascual Carolina Segura-Morales Manja Omerzu Nicolás Bellora Eulàlia Belloc

Transition through cell cycle phases requires temporal and spatial regulation of gene expression to ensure accurate chromosome duplication and segregation. This regulation involves dynamic reprogramming of gene expression at multiple transcriptional and posttranscriptional levels. In transcriptionally silent oocytes, the CPEB-family of RNA-binding proteins coordinates temporal and spatial translation regulation of stored maternal mRNAs to drive meiotic progression. CPEB1 mediates mRNA localization to the meiotic spindle, which is required to ensure proper chromosome segregation. Temporal translational regulation also takes place in mitosis, where a large repertoire of transcripts is activated or repressed in specific cell cycle phases. However, whether control of localized translation at the spindle is required for mitosis is unclear, as mitotic and acentriolar-meiotic spindles are functionally and structurally different. Furthermore, the large differences in scale-ratio between cell volume and spindle size in oocytes compared to somatic mitotic cells may generate distinct requirements for gene expression compartmentalization in meiosis and mitosis. Here we show that mitotic spindles contain CPE-localized mRNAs and translating ribosomes. Moreover, CPEB1 and CPEB4 localize in the spindles and they may function sequentially in promoting mitotic stage transitions and correct chromosome segregation. Thus, CPEB1 and CPEB4 bind to specific spindle-associated transcripts controlling the expression and/or localization of their encoded factors that, respectively, drive metaphase and anaphase/cytokinesis.

Spindle pole body

10.1261/rna.077552.120

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Borrelia burgdorferi is strong inducer of IFN-γ production by human primary NK cells

Cytokine (2022)

Marije Oosting Michelle A. E. Brouwer Hedwig D. Vrijmoeth Rosa Pascual Anna Greco

Natural Killer (NK) cells belong to the innate lymphoid lineage and are highly present in the human skin. NK cells can produce a range of pro-inflammatory mediators, including cytokines and chemokines. The role of NK(-T) cells in the immune response towards Borrelia burgdorferi infection was studied. The production of interleukin (IL)-6, IL-1β and interferon-gamma (IFN-γ) by human primary peripheral blood mononuclear cells (PBMCs) exposed to B. burgdorferi was assessed. Interestingly, CD56+ (NK + NK-T) cells were the only cells within the PBMC-fraction that produced IFN-γ during the first 24 h of stimulation. Within the NK(-T) cell fraction, NK cells seemed to be responsible for the IFN-γ production. Since it was previously demonstrated that both TLR2 and NOD2 receptors are involved in the recognition of B. burgdorferi, the expression of both TLR2 and NOD2 mRNA on NK cells was determined. In contrast to TLR2, NOD2 mRNA was upregulated on CD56+ (NK + NK-T) cells after Borrelia exposure. Finally, to unravel the mechanisms underlying erythema migrans (EM) development, crosstalk between CD56+ (NK + NK-T) cells and keratinocytes was investigated. CD56+ (NK + NK-T) cells activated by B. burgdorferi produced soluble mediators strongly inducing the expression of antimicrobial peptides, such as β-defensin-2 and psoriasin in human keratinocytes. In conclusion, CD56+ (NK + NK-T) cells produced IFN-γ shortly after exposure to B. burgdorferi and released soluble mediators that were able to activate keratinocytes. These observations underscore the important role of CD56+ (NK + NK-T) cells during early host defence when Borrelia burgdorferi enters the human skin during a tick bite.

Janus kinase 3

10.1016/j.cyto.2022.155895

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The RNA binding protein CPEB2 regulates hormone sensing in mammary gland development and luminal breast cancer

Science Advances (2020)

Rosa Pascual Judit Martín Fernando Salvador Oscar Reina Verónica Chanes

The RNA binding protein CPEB2 defines a new posttranscriptional layer in the hormone-driven gene-expression reprogramming.

Reprogramming

10.1126/sciadv.aax3868

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Citations (16)