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Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis

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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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Figure 1: NSPCs are in a distinct metabolic state and require Fasn-dependent lipogenesis for proliferation.
Figure 2: Spot14 is expressed in adult hippocampal NSPCs.
Figure 3: Spot14 regulates proliferative activity of adult NSPCs.
Figure 4: Spot14 modulates malonyl-CoA levels and de novo lipogenesis.

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Primary accessions

Gene Expression Omnibus

Data deposits

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

Change history

  • 09 January 2013

    The accession number in the original PDF was corrected.

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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.

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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.

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Correspondence to Sebastian Jessberger.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12, a Supplementary Discussion, Supplementary Methods and Supplementary References. (PDF 9177 kb)

Supplementary Tables

This file contains Supplementary Tables 1-6. (XLS 358 kb)

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 (MOV 1347 kb)

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. (MOV 935 kb)

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. (MOV 1689 kb)

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. (MOV 1229 kb)

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Knobloch, M., Braun, S., Zurkirchen, L. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013). https://doi.org/10.1038/nature11689

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