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
(Publisher version, Peer reviewed)