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Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

Florian Villegas 1, 2 Daphne Lehalle 3, 4, 5, 6 Daniela Mayer 1, 2 Melanie Rittirsch 1 Michael Stadler 7, 1 Marietta Zinner 1, 2 Daniel Olivieri 1 Pierre Vabres 3, 5, 6, 8 Laurence Duplomb-Jego 5, 6 Eveline de Bont 9 Yannis Duffourd 5, 6 Floor Duijkers 10 Magali Avila 5, 6 David Geneviève 11 Nada Houcinat 3, 5, 6, 4 Thibaud Jouan 5, 6 Paul Kuentz 3, 5, 6, 4 Klaske Lichtenbelt 12 Christel Thauvin-Robinet 3, 5, 6, 4 Judith St-Onge 5, 6, 13 Julien Thevenon 3, 5, 6, 4 Koen van Gassen 12 Mieke van Haelst 10 Silvana van Koningsbruggen 10 Daniel Hess 1 Sébastien Smallwood 1 Jean-Baptiste Rivière 5, 6 Laurence Faivre 3, 5, 6, 4 Joerg Betschinger 1, *
* Auteur correspondant
1 FMI - Friedrich Miescher Institute for Biomedical Research
2 Unibas - University of Basel
3 FHU TRANSLAD (CHU de Dijon)
4 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
5 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
6 UBFC - Université Bourgogne Franche-Comté [COMUE]
7 SIB - Swiss Institute of Bioinformatics [Lausanne]
8 Service de Dermatologie (CHU de Dijon)
9 Beatrix Children's Hospital
10 Department of Clinical Genetics (Academic Medical Center, University of Amsterdam)
11 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
12 University Medical Center [Utrecht]
13 Research Institute of the McGill University Hospital Centre
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.
Keywords : pluripotency mTOR Flcn Rag GTPases Ragulator Tfe3 developmental disorder differentiation embryonic stem cell
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-02005576
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Soumis le : lundi 4 février 2019 - 11:04:16
Dernière modification le : jeudi 20 janvier 2022 - 14:18:33

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UNIV-BOURGOGNE | LNC-UMR866 | LNC-GAD

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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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