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RESEARCH PRODUCT
Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
Paul KuentzMagali AvilaJean Baptiste RivièreJean Baptiste RivièreJean Baptiste RivièrePierre VabresMarietta ZinnerMarietta ZinnerJulien ThevenonJudith St-ongeJudith St-ongeDavid GenevièveEveline S. J. M. De BontFlorian VillegasFlorian VillegasFloor A. M. DuijkersMieke M. Van HaelstLaurence DuplombSébastien A. SmallwoodSilvana Van KoningsbruggenDaniel OlivieriNada HoucinatYannis DuffourdThibaud JouanChristel Thauvin-robinetKoen L.i. Van GassenDaphné LehalleMelanie RittirschMichael B. StadlerMichael B. StadlerLaurence FaivreDaniel HessKlaske D. LichtenbeltJoerg BetschingerDaniela MayerDaniela Mayersubject
MaleTranscription GeneticGTPaseGTP PhosphohydrolasesPATHWAYMice0302 clinical medicineNeural Stem CellsCRISPRTUMOR-SUPPRESSORCell Self RenewalPhosphorylationSPECIFICATIONdevelopmental disorder0303 health sciencesGenomeBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCell DifferentiationMouse Embryonic Stem CellsFlcndifferentiationCell biologymedicine.anatomical_structuremTORMolecular MedicineFemaleSignal transductionProtein BindingSignal TransductionRECRUITMENTBiology03 medical and health sciencesRag GTPasesLysosomeGeneticsmedicineAnimalsHumansPoint MutationNAIVE PLURIPOTENCYAMINO-ACID LEVELSTranscription factorAllelesPI3K/AKT/mTOR pathway030304 developmental biologyCOMPLEXFOLLICULINRagulatorCell Biologypluripotencyembryonic stem cellEmbryonic stem cellTfe3[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human geneticsCytoplasmLysosomes030217 neurology & neurosurgerydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-02-07 | Cell Stem Cell |