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Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

2018; Elsevier BV; Volume: 24; Issue: 2 Linguagem: Inglês

10.1016/j.stem.2018.11.021

1934-5909

Florian Villegas, Daphné Lehalle, Daniela Mayer, Melanie Rittirsch, Michael Stadler, Marietta Zinner, Daniel Olivieri, P. Vabres, Laurence Duplomb, Eveline S.J.M. de Bont, Yannis Duffourd, Floor A.M. Duijkers, Magali Avila, David Geneviève, Nada Houcinat, Thibaud Jouan, Paul Kuentz, Klaske D. Lichtenbelt, Christel Thauvin‐Robinet, Judith St‐Onge, Julien Thévenon, Koen L.I. van Gassen, Mieke M. van Haelst, Silvana van Koningsbruggen, Daniel Heß, Sébastien A. Smallwood, Jean‐Baptiste Rivière, Laurence Faivre, Joerg Betschinger,

Cellular transport and secretion

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.