Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3.
Cell Stem Cell
; 24(2): 257-270.e8, 2019 02 07.
Article
em En
| MEDLINE
| ID: mdl-30595499
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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MEDLINE
Assunto principal:
Transdução de Sinais
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Diferenciação Celular
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
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Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article