Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
Villegas, Florian; Lehalle, Daphné; Mayer, Daniela; Rittirsch, Melanie; Stadler, Michael B.; Zinner, Marietta; Olivieri, Daniel; Vabres, Pierre; Duplomb-Jego, Laurence; De Bont, Eveline S.J.M.; Duffourd, Yannis; Duijkers, Floor; Avila, Magali; Geneviève, David; Houcinat, Nada; Jouan, Thibaud; Kuentz, Paul; Lichtenbelt, Klaske D.; Thauvin-Robinet, Christel; St-Onge, Judith; Thevenon, Julien; van Gassen, Koen L.I.; van Haelst, Mieke; van Koningsbruggen, Silvana; Hess, Daniel; Smallwood, Sebastien A.; Rivière, Jean Baptiste; Faivre, Laurence; Betschinger, Joerg
(2019) Cell Stem Cell, volume 24, issue 2, pp. 257 - 270.e8
(Article)
Abstract
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
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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.
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Keywords: developmental disorder, differentiation, embryonic stem cell, Flcn, mTOR, pluripotency, Rag GTPases, Ragulator, Tfe3, Molecular Medicine, Genetics, Cell Biology
ISSN: 1934-5909
Publisher: Cell Press
Note: Funding Information: We would like to thank the patients and families who participated in this study. We also thank the University of Burgundy Centre de Calcul (CCuB) for technical support and management of the informatics platform; S. Dessus-Babus, K. Jacobeit, and T. Roloff (FMI) for processing sequencing samples; L. Gelman (FMI) for imaging assistance; H. Gut (FMI) for structural modelling; M. Flemr (FMI) for advice regarding genome editing; J. Chao (FMI), A. Smith (University of Cambridge), F. Stewart (University of Dresden), K. Yusa (Wellcome Trust Sanger Institute), and M. Leeb (MFPL) for providing reagents; and S. Gasser, P. Liberali, A. Peters, D. Schuebeler, N. Thomae (FMI), S. Stricker (Helmholtz Zentrum), and D. Teis (University of Innsbruck) for comments on the manuscript. This work was funded by EMBO and Marie Curie Actions ( ALTF 1632-2014 to D.O.), the Programme Hospitalier de Recherche Clinique (PHRC) National (to P.V.), the Regional Council of Burgundy and Centre Hospitalo-Universitaire de Dijon PARI 2015 (to L.F.), and the Novartis Research Foundation (to J.B.). Funding Information: We would like to thank the patients and families who participated in this study. We also thank the University of Burgundy Centre de Calcul (CCuB) for technical support and management of the informatics platform; S. Dessus-Babus, K. Jacobeit, and T. Roloff (FMI) for processing sequencing samples; L. Gelman (FMI) for imaging assistance; H. Gut (FMI) for structural modelling; M. Flemr (FMI) for advice regarding genome editing; J. Chao (FMI), A. Smith (University of Cambridge), F. Stewart (University of Dresden), K. Yusa (Wellcome Trust Sanger Institute), and M. Leeb (MFPL) for providing reagents; and S. Gasser, P. Liberali, A. Peters, D. Schuebeler, N. Thomae (FMI), S. Stricker (Helmholtz Zentrum), and D. Teis (University of Innsbruck) for comments on the manuscript. This work was funded by EMBO and Marie Curie Actions (ALTF 1632-2014 to D.O.), the Programme Hospitalier de Recherche Clinique (PHRC) National (to P.V.), the Regional Council of Burgundy and Centre Hospitalo-Universitaire de Dijon PARI 2015 (to L.F.), and the Novartis Research Foundation (to J.B.). Publisher Copyright: © 2018 Elsevier Inc.
(Peer reviewed)