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

Nat Neurosci. 2010 Nov;13(11):1365-72. doi: 10.1038/nn.2644. Epub 2010 Oct 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Brain / cytology
  • Brain / 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
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / pharmacology
  • Nestin
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Stem Cells / physiology*
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / physiology*


  • 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