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Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

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 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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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-02005576
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : lundi 4 février 2019 - 11:04:16
Dernière modification le : vendredi 15 mai 2020 - 12:22:10

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Florian Villegas, Daphne Lehalle, Daniela Mayer, Melanie Rittirsch, Michael Stadler, et al.. Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3. Cell Stem Cell, Cambridge, MA : Cell Press, 2019, 24 (2), pp.257-270.e8. ⟨10.1016/j.stem.2018.11.021⟩. ⟨hal-02005576⟩

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