Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3.

Alleles Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism Cell Differentiation Cell Self Renewal Female GTP Phosphohydrolases / metabolism Genome Humans Lysosomes / metabolism Male Mice Mouse Embryonic Stem Cells / cytology Neural Stem Cells / cytology Phosphorylation Point Mutation / genetics Protein Binding Signal Transduction Transcription, Genetic

Flcn Rag GTPases Ragulator Tfe3 developmental disorder differentiation embryonic stem cell mTOR pluripotency

Journal

Cell stem cell

ISSN: 1875-9777

Titre abrégé: Cell Stem Cell

Pays: United States

ID NLM: 101311472

Informations de publication

Date de publication:
07 02 2019

Historique:

received: 29 11 2017

revised: 21 09 2018

accepted: 20 11 2018

pubmed: 1 1 2019

medline: 28 3 2020

entrez: 1 1 2019

Statut: ppublish

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.

Identifiants

DOI: 10.1016/j.stem.2018.11.021 PMID: 30595499

pubmed: 30595499

pii: S1934-5909(18)30557-5

doi: 10.1016/j.stem.2018.11.021

pii:

doi:

Substances chimiques

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors 0

Tcfe3 protein, mouse 136896-33-8

GTP Phosphohydrolases EC 3.6.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

257-270.e8

Commentaires et corrections

Type : CommentIn