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PMID: 20935640 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun.

Nature neuroscience ·Vol. 13 ·No. 11 ·2010-11-00 ·Pages 1365-72

Hoeck JD, Jandke A, Blake SM, Nye E, Spencer-Dene B, Brandner S, Behrens A

Abstract

Neural stem and progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes and oligodendrocytes. However, the mechanisms underlying the decision of a stem cell to either self-renew or differentiate are incompletely understood. We demonstrate here that Fbw7 (F-box and WD repeat domain containing-7), the substrate recognition component of an SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase, is a key regulator of NSC/NPC viability and differentiation. The absence of Fbw7 in the mouse brain caused severely impaired stem cell differentiation and increased progenitor cell death. Fbw7 deficiency resulted in accumulation of two SCF(Fbw7) substrates, the transcription factors active Notch1 and N-terminally phosphorylated c-Jun. Genetic and pharmacological rescue experiments identified c-Jun as a key substrate of Fbw7 in controlling progenitor cell viability, whereas inhibition of Notch signaling alleviated the block in stem cell differentiation. Thus Fbw7 controls neurogenesis by antagonizing Notch and c-Jun N-terminal kinase (JNK)/c-Jun signaling.

MeSH Terms
Animals Apoptosis/physiology Brain/cytology,embryology Cell Differentiation/physiology Cell Proliferation Cells, Cultured Embryo, Mammalian F-Box Proteins/physiology F-Box-WD Repeat-Containing Protein 7 Gene Expression Regulation, Developmental/physiology Humans Intermediate Filament Proteins/metabolism Mice Mice, Transgenic Nerve Tissue Proteins/genetics,metabolism,pharmacology Nestin Proto-Oncogene Proteins c-jun/genetics,metabolism Receptors, Notch/genetics,metabolism Stem Cells/physiology Ubiquitin-Protein Ligases/deficiency,physiology
Chemicals
F-Box Proteins F-Box-WD Repeat-Containing Protein 7 Fbxw7 protein, mouse Intermediate Filament Proteins NES protein, human Nerve Tissue Proteins Nes protein, mouse Nestin Proto-Oncogene Proteins c-jun Receptors, Notch Ubiquitin-Protein Ligases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Hoeck Joerg D
Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London, UK.
Jandke Anett
Blake Sophia M
Nye Emma
Spencer-Dene Bradley
Brandner Sebastian
Behrens Axel
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.2644
Published
2010-11-00
Epub
2010-00-10
Pages
1365-72
Language
English
Region
United States
NLM ID
9809671
Subset
IM
Grants
Medical Research Council · G0800020 · United Kingdom
Cancer Research UK · United Kingdom
Medical Research Council · 85704 · United Kingdom
Corrections
CommentIn
PMID: 20975753
External Links
PubMed source DOI: 10.1038/nn.2644 View journal details
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