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

Nature Neuroscience volume 13, pages 1365–1372 (2010)Cite this article

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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.

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Figure 1: Fbw7 controls cell number and survival in the brain.
Figure 2: Fbw7 controls stem cell differentiation and neurogenesis in the brain.
Figure 3: Absence of Fbw7 leads to retention of markers for immature cells and induces apoptosis in vitro.
Figure 4: Absence of Fbw7 blocks differentiation in vitro.
Figure 5: Negative regulation of c-Jun by Fbw7 controls neural cell viability.
Figure 6: Fbw7 controls stem cell differentiation by antagonizing Notch.

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Acknowledgements

We are grateful to the Animal Unit, Equipment Park, FACS Lab and the Experimental Pathology Lab at the London Research Institute for technical help and advice on histology. We are grateful to F. Radtke (Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland) for floxed Notch1 mice. We thank R. Sancho for the data on Fbxw7 isoform expression in various tissues. We thank C.R. Da Costa, S. Marino and A. Martin-Villalba for critical reading of the manuscript. S.M.B. is supported by a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Long Term Fellowship. Part of this work is supported by an MRC project grant (85704) to A.B. The London Research Institute is funded by Cancer Research UK.

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Authors and Affiliations

  1. Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London, UK

    Joerg D Hoeck, Anett Jandke, Sophia M Blake & Axel Behrens

  2. Experimental Pathology Laboratory, Cancer Research UK London Research Institute, London, UK

    Emma Nye & Bradley Spencer-Dene

  3. Division of Neuropathology, Department of Neurodegenerative Disease, University College London, Institute of Neurology, London, UK

    Sebastian Brandner

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Contributions

J.D.H. designed and conducted the majority of the experiments, did the data analyses and co-wrote the manuscript. A.J. generated the Fbxw7f/f mice and performed the radioactive in situ hybridization. S.M.B. performed the experiments on adherent NSC cultures. E.N. did the IHC stainings. B.S.-D. performed the nonradioactive in situ hybridization. S.B. gave advice on neurosphere sectioning. A.B. supervised the project, directed the experiments and wrote the manuscript.

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Correspondence to Axel Behrens.

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Hoeck, J., Jandke, A., Blake, S. et al. Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun. Nat Neurosci 13, 1365–1372 (2010). https://doi.org/10.1038/nn.2644

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