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Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

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Villegas, Florian | Lehalle, Daphne | Mayer, Daniela | Rittirsch, Melanie | Stadler, Michael | 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 | van Haelst, Mieke, M. | van Koningsbruggen, Silvana | Hess, Daniel | Smallwood, Sébastien, A. | Rivière, Jean-Baptiste | Faivre, Laurence | Betschinger, Joerg

Edité par CCSD ; Cambridge, MA : Cell Press -

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.

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