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Abstract

Mechanisms controlling the proliferative activity of neural stem and progenitor cells (NSPCs) have a pivotal role to ensure life-long neurogenesis in the mammalian brain1. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (Fasn), the key enzyme of de novo lipogenesis2, is highly active in adult NSPCs and that conditional deletion of Fasn in mouse NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene previously implicated in lipid metabolism3,4,5, that we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA6, which is an essential substrate for Fasn to fuel lipogenesis. Thus, we identify here a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation.

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Change history

  • 09 January 2013

    The accession number in the original PDF was corrected.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in the Gene Expression Omnibus under accession number GSE27391.

References

  1. 1.

    , & Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008)

  2. 2.

    , & Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science 311, 1258–1262 (2006)

  3. 3.

    et al. Spot 14 gene deletion increases hepatic de novo lipogenesis. Endocrinology 142, 4363–4370 (2001)

  4. 4.

    , , , & The “Spot 14” gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers: implications for control of tumor metabolism. Proc. Natl Acad. Sci. USA 95, 6989–6994 (1998)

  5. 5.

    , & Human spot 14 glucose and thyroid hormone response: characterization and thyroid hormone response element identification. Endocrinology 144, 5242–5248 (2003)

  6. 6.

    et al. Crystal structure of Spot 14, a modulator of fatty acid synthesis. Proc. Natl Acad. Sci. USA 107, 18820–18825 (2010)

  7. 7.

    , & Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679–683 (2005)

  8. 8.

    et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010)

  9. 9.

    , & Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010)

  10. 10.

    et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2010)

  11. 11.

    & Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer 7, 763–777 (2007)

  12. 12.

    et al. Brain fatty acid synthase activates PPARα to maintain energy homeostasis. J. Clin. Invest. 117, 2539–2552 (2007)

  13. 13.

    et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J. Neurosci. 27, 12623–12629 (2007)

  14. 14.

    et al. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell 1, 515–528 (2007)

  15. 15.

    , , , & Enhancing the reliability and throughput of neurosphere culture on hydrogel microwell arrays. Stem Cells 26, 2586–2594 (2008)

  16. 16.

    et al. Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proc. Natl Acad. Sci. USA 107, 9626–9631 (2010)

  17. 17.

    , , , & Overlapping roles of the glucose-responsive genes, S14 and S14R, in hepatic lipogenesis. Endocrinology 151, 2071–2077 (2010)

  18. 18.

    , , & Visualization of neurogenesis in the central nervous system using nestin promoter–GFP transgenic mice. Neuroreport 11, 1991–1996 (2000)

  19. 19.

    et al. Building a zoo of mice for genetic analyses: a comprehensive protocol for the rapid generation of BAC transgenic mice. Genesis 48, 264–280 (2010)

  20. 20.

    et al. Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 108, 5807–5812 (2011)

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Acknowledgements

We thank S. Aigner, D. C. Lie, F. H. Gage and members of the Jessberger group for conceptual input; S. Kobel, C. Fischer, K. Walter, P. Sidiropoulos, T. Buch, B. Becher, P. Pelczar, P. Lötscher, A. J. Eisch and D. C. Lagace for experimental help or reagents; and the Light Microscopy and Screening Center (LMSC) of the ETH Zurich and the BioImaging and Optics Platform (BIOP) of the EPFL for help with imaging. This study was supported by the NCCR Neural Plasticity and Repair, Swiss National Science Foundation, TH grant (ETH-01 08-1), Zurich Neuroscience Center (ZNZ), Novartis Foundation, Theodore Ott Foundation, and the EMBO Young Investigator program (to S.J.). M.K. was supported by the Janggen-Pöhn foundation.

Author information

Author notes

    • Marlen Knobloch
    •  & Simon M. G. Braun

    These authors contributed equally to this work.

Affiliations

  1. Brain Research Institute, Faculty of Medicine, University of Zurich, 8057 Zurich, Switzerland

    • Marlen Knobloch
    • , Simon M. G. Braun
    • , Raquel A. C. Machado
    •  & Sebastian Jessberger
  2. Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland

    • Marlen Knobloch
    • , Simon M. G. Braun
    • , Luis Zurkirchen
    • , Carolin von Schoultz
    • , Werner J. Kovacs
    • , Özlem Karalay
    • , Ueli Suter
    • , Raquel A. C. Machado
    •  & Sebastian Jessberger
  3. Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland

    • Nicola Zamboni
  4. Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany

    • Marcos J. Araúzo-Bravo
  5. Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland

    • Marta Roccio
    •  & Matthias P. Lutolf
  6. Washington University School of Medicine, Division of Endocrinology, Metabolism & Lipid Research, St. Louis, Missouri 63110, USA

    • Clay F. Semenkovich

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Contributions

M.K. contributed to the concept, carried out experiments, analysed data and co-wrote the paper. S.M.G.B. carried out experiments and analysed data. L.Z., C.v.S. and R.A.C.M. carried out experiments. N.Z. carried out the metabolomics experiments. M.J.A.B. analysed the array data. M.R. and M.P.L. contributed to the time-lapse imaging of NSPCs. W.J.K. contributed to the lipid metabolism experiments. Ö.K., U.S. and C.F.S. provided reagents. All authors revised the manuscript. S.J. developed the concept and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sebastian Jessberger.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-12, a Supplementary Discussion, Supplementary Methods and Supplementary References.

Excel files

  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-6.

Videos

  1. 1.

    Video 1: Single-cell imaging of Spot14+ NSPC in vitro (example 1)

    Shown is a time lapse imaging of a single Spot14 positive NSPC captured in a hydrogel-based microwell over 81h. The cell is alive throughout the time observed but does not divide, illustrating the more quiescent nature of Spot14 positive NSPCs

  2. 2.

    Video 2: Single-cell imaging of Spot14+ NSPC in vitro (example 2)

    Shown is a time lapse imaging of a single Spot14 positive NSPC captured in a hydrogel-based microwell over 81h. The cell is alive throughout the time observed but does not divide.

  3. 3.

    Video 3: Single-cell imaging of Spot14- NSPC in vitro (example 1)

    Shown is a time lapse imaging of a single Spot14 negative NSPC captured in a hydrogel-based microwell over 81h. The cell is dividing several times throughout the time observed, illustrating the more proliferative nature of Spot14 negative NSPCs compared to Spot14 positive NSPCs.

  4. 4.

    Video 4: Single-cell imaging of Spot14- NSPC in vitro (example 2)

    Shown is a time lapse imaging of a single Spot14 negative NSPC captured in a hydrogel-based microwell over 81h. The cell is dividing several times throughout the time observed.

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DOI

https://doi.org/10.1038/nature11689

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