دورية أكاديمية
أعرض في EDS

Multiscale modeling uncovers 7q11.23 copy number variation-dependent changes in ribosomal biogenesis and neuronal maturation and excitability.

التفاصيل البيبلوغرافية
العنوان: Multiscale modeling uncovers 7q11.23 copy number variation-dependent changes in ribosomal biogenesis and neuronal maturation and excitability.
المؤلفون: Mihailovich M; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy., Germain PL; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Computational Neurogenomics, D-HEST Institute for Neuroscience, Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland., Shyti R; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy., Pozzi D; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; IRCCS Humanitas Research Hospital, Milan, Italy., Noberini R; European Institute of Oncology (IEO) IRCCS, Milan, Italy., Liu Y; Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland., Aprile D; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Tenderini E; European Institute of Oncology (IEO) IRCCS, Milan, Italy., Troglio F; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Trattaro S; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Fabris S; Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Ciptasari U; Department of Cognitive Neurosciences, RadboudUmc, Donders Institute for Brain Cognition and Behaviour, Nijmegen, Netherlands., Rigoli MT; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Caporale N; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., D'Agostino G; European Institute of Oncology (IEO) IRCCS, Milan, Italy., Mirabella F; Human Technopole, Milan, Italy., Vitriolo A; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Capocefalo D; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Skaros A; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy., Franchini AV; European Institute of Oncology (IEO) IRCCS, Milan, Italy., Ricciardi S; Department of Biosciences, University of Milan, Milan, Italy.; National Institute of Molecular Genetics, Fondazione Romeo ed Enrica Invernizzi, Milan, Italy., Biunno I; Integrated Systems Engineering Srl, c/o OpenZone, Bresso, Milan, Italy., Neri A; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.; Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Nadif Kasri N; Department of Cognitive Neurosciences, RadboudUmc, Donders Institute for Brain Cognition and Behaviour, Nijmegen, Netherlands., Bonaldi T; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Aebersold R; Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland., Matteoli M; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; IRCCS Humanitas Research Hospital, Milan, Italy., Testa G; European Institute of Oncology (IEO) IRCCS, Milan, Italy.; Human Technopole, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
المصدر: The Journal of clinical investigation [J Clin Invest] 2024 Jul 15; Vol. 134 (14). Date of Electronic Publication: 2024 Jul 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: DNA Copy Number Variations* , Neurons*/metabolism , Neurons*/pathology , Chromosomes, Human, Pair 7*/genetics, Humans ; Ribosomes/metabolism ; Ribosomes/genetics ; Neurogenesis/genetics ; Williams Syndrome/genetics ; Williams Syndrome/metabolism ; Williams Syndrome/pathology ; Williams Syndrome/physiopathology ; Ribosomal Protein S6/metabolism ; Ribosomal Protein S6/genetics ; TOR Serine-Threonine Kinases/metabolism ; TOR Serine-Threonine Kinases/genetics ; Male ; Cell Differentiation ; Female
مستخلص: Copy number variation (CNV) at 7q11.23 causes Williams-Beuren syndrome (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics, and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are posttranscriptionally buffered. Consistently, we found phosphorylated RPS6 (p-RPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, p-4EBP was changed in the opposite direction, reflecting dosage-specific changes in total 4EBP levels. This highlights different dosage-sensitive dyregulations of the mTOR pathway as well as distinct roles of p-RPS6 and p-4EBP during neurogenesis. Our work demonstrates the importance of multiscale disease modeling across molecular and functional layers, uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs, and uncouples the roles of p-RPS6 and p-4EBP as mechanistically actionable relays in NDDs.
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فهرسة مساهمة: Keywords: Neurodevelopment; Neuroscience; Psychiatric diseases; Stem cells; Translation
المشرفين على المادة: 0 (Ribosomal Protein S6)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
EC 2.7.1.1 (MTOR protein, human)
تواريخ الأحداث: Date Created: 20240715 Date Completed: 20240715 Latest Revision: 20240717
رمز التحديث: 20240717
مُعرف محوري في PubMed: PMC11245157
DOI: 10.1172/JCI168982
PMID: 39007270
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI168982