1. Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
- Author
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Paul Kuentz, Magali Avila, Jean Baptiste Rivière, Pierre Vabres, Marietta Zinner, Julien Thevenon, Judith St-Onge, David Geneviève, Eveline S. J. M. de Bont, Florian Villegas, Floor A. M. Duijkers, Mieke M. van Haelst, Laurence Duplomb-Jego, Sébastien A. Smallwood, Silvana van Koningsbruggen, Daniel Olivieri, Nada Houcinat, Yannis Duffourd, Thibaud Jouan, Christel Thauvin-Robinet, Koen L.I. van Gassen, Daphné Lehalle, Melanie Rittirsch, Michael B. Stadler, Laurence Faivre, Daniel Hess, Klaske D. Lichtenbelt, Joerg Betschinger, Daniela Mayer, Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, University of Basel (Unibas), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Service de Dermatologie (CHU de Dijon), Beatrix Children's Hospital, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Research Institute of the McGill University Hospital Centre, Human genetics, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Human Genetics, and ACS - Pulmonary hypertension & thrombosis
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Male ,Transcription, Genetic ,GTPase ,GTP Phosphohydrolases ,PATHWAY ,Mice ,0302 clinical medicine ,Neural Stem Cells ,CRISPR ,TUMOR-SUPPRESSOR ,Cell Self Renewal ,Phosphorylation ,SPECIFICATION ,developmental disorder ,0303 health sciences ,Genome ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Cell Differentiation ,Mouse Embryonic Stem Cells ,Flcn ,differentiation ,Cell biology ,medicine.anatomical_structure ,mTOR ,Molecular Medicine ,Female ,Signal transduction ,Protein Binding ,Signal Transduction ,RECRUITMENT ,Biology ,03 medical and health sciences ,Rag GTPases ,Lysosome ,Genetics ,medicine ,Animals ,Humans ,Point Mutation ,NAIVE PLURIPOTENCY ,AMINO-ACID LEVELS ,Transcription factor ,Alleles ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,COMPLEX ,FOLLICULIN ,Ragulator ,Cell Biology ,pluripotency ,embryonic stem cell ,Embryonic stem cell ,Tfe3 ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Cytoplasm ,Lysosomes ,030217 neurology & neurosurgery - Abstract
International audience; Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino-acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm. In contrast, ectopic nuclear Tfe3 represses specific developmental and metabolic transcriptional programs that are associated with peri-implantation development. We show differentiation-specific and non-canonical regulation of Rag GTPase in ESCs and, importantly, identify point mutations in a Tfe3 domain required for cytoplasmic inactivation as potentially causal for a human developmental disorder. Our work reveals an instructive and biomedically relevant role of metabolic signaling in licensing embryonic cell fate transitions.
- Published
- 2019
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