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

Joerg D Hoeck (1) , Anett Jandke (1) , Sophia Maria Blake (1) , Emma Nye (1) , Bradley Spencer-Dene (1) , Sebastian Brandner (1) , Axel Behrens (1)

1 Mammalian Genetics Laboratory

Neural stem/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 murine NSC/NPC viability and differentiation. The absence of Fbw7 caused severely impaired stem cell differentiation and increased progenitor cell death. Fbw7 deficiency resulted in accumulation of the SCF(Fbw7) substrates 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 signalling alleviated the block in stem cell differentiation. Thus Fbw7 controls neurogenesis by antagonising Notch and JNK/c-Jun signalling.

Mots clés: Signal Transduction; Development; Differentiation

Joerg D Hoeck, Anett Jandke, Sophia Maria Blake, Emma Nye, Bradley Spencer-Dene, et al.. Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nature Neuroscience, 2010, ⟨10.1038/nn.2644⟩. ⟨hal-00584724⟩