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 S.J.M de Bont
(9, 10)
,
Yannis Duffourd
(5, 6)
,
Floor Duijkers
(11, 12)
,
Magali Avila
(5, 6)
,
David Geneviève
(13)
,
Nada Houcinat
(3, 5, 6, 4)
,
Thibaud Jouan
(5, 6)
,
Paul Kuentz
(3, 5, 6, 4)
,
Klaske D. Lichtenbelt
(14)
,
Christel Thauvin-Robinet
(3, 5, 6, 4)
,
Judith St-Onge
(5, 6, 15, 16)
,
Julien Thevenon
(3, 5, 6, 4)
,
Koen L van Gassen
(14)
,
Mieke M. van Haelst
(11, 12)
,
Silvana van Koningsbruggen
(11, 12)
,
Daniel Hess
(1)
,
Sébastien A. Smallwood
(1)
,
Jean-Baptiste Rivière
(5, 6)
,
Laurence Faivre
(3, 5, 6, 4)
,
Joerg Betschinger
(1)
1
FMI -
Friedrich Miescher Institute for Biomedical Research
2 Unibas - Université de Bâle = 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)
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 UMCG - University Medical Center Groningen [Groningen]
11 Department of Clinical Genetics (Academic Medical Center, University of Amsterdam)
12 VU University Medical Center [Amsterdam]
13 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
14 University Medical Center [Utrecht]
15 Research Institute of the McGill University Hospital Centre
16 MUHC - McGill University Health Center [Montreal]
2 Unibas - Université de Bâle = 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)
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 UMCG - University Medical Center Groningen [Groningen]
11 Department of Clinical Genetics (Academic Medical Center, University of Amsterdam)
12 VU University Medical Center [Amsterdam]
13 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
14 University Medical Center [Utrecht]
15 Research Institute of the McGill University Hospital Centre
16 MUHC - McGill University Health Center [Montreal]
Pierre Vabres
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Laurence Duplomb-Jego
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Yannis Duffourd
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Thibaud Jouan
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Jean-Baptiste Rivière
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Joerg Betschinger
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Résumé
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.