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Latent tri-lineage potential of adult hippocampal neural stem cells revealed by Nf1 inactivation

Nature Neuroscience volume 18, pages 1722–1724 (2015)Cite this article

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Abstract

Endogenous neural stem cells (NSCs) in the adult hippocampus are considered to be bi-potent, as they only produce neurons and astrocytes in vivo. In mouse, we found that inactivation of neurofibromin 1 (Nf1), a gene mutated in neurofibromatosis type 1, unlocked a latent oligodendrocyte lineage potential to produce all three lineages from NSCs in vivo. Our results suggest an avenue for promoting stem cell plasticity by targeting barriers of latent lineage potential.

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Figure 1: NestinCreERT2-based conditional Nf1 inactivation in adult hippocampal neural progenitors leads to generation of oligodendrocyte progenitor cells.
Figure 2: Clonal lineage-tracing of RGLs following conditional Nf1 inactivation reveals RGLs as OPC cell of origin.

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Acknowledgements

We thank members of the Ming and Song laboratories for discussion, and Y. Cai and L. Liu for technical support. This work was supported by the US National Institutes of Health (NS047344 to H.S., NS080913 to M.A.B., and NS048271 and MH105128 to G.M.), and by a pre-doctoral fellowship from The Children's Tumor Foundation to G.J.S.

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Authors and Affiliations

  1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Gerald J Sun, Yi Zhou, Shiori Ito, Michael A Bonaguidi, Nicholas K Kawasaki, Nikhil Modak, Guo-li Ming & Hongjun Song

  2. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Gerald J Sun, Guo-li Ming & Hongjun Song

  3. Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Yi Zhou, Guo-li Ming & Hongjun Song

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Michael A Bonaguidi, Guo-li Ming & Hongjun Song

  5. Pre-doctoral Human Genetics Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Genevieve Stein-O'Brien & Hongjun Song

  6. Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC, USA

    Yuan Zhu

  7. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Guo-li Ming

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  1. Gerald J Sun
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Contributions

G.J.S., H.S. and G.M. designed the project. G.J.S. contributed to all aspects of the study. Y. Zhou, S.I., G.S.-O'B., N.K.K. and N.M. performed the experiments. M.A.B. provided some initial data. Y. Zhu contributed reagents. G.J.S., H.S. and G.M. wrote the manuscript.

Corresponding authors

Correspondence to Guo-li Ming or Hongjun Song.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Inducible recombination and cell targeting of Nf1 inactivation in NSCs at the population level using Nestin-CreERT2 mice.

(a) Genetic recombination model for conditional inactivation of Nf1 in the adult mouse brain. (b) Injection timeline and paradigm for population analysis using NestinCreERT2-based cell targeting. (c) Sample confocal image of GFP+ cells in Nf1Nestin animal at 1 mpi. Arrowheads point to GFP+MCM2+NG2+ OPCs. (d) Sample confocal image of an ectopically Olig2-expressing RGL in Nf1Nestin animal at 14 dpi. Scale bars: 10 μm.

Supplementary Figure 2 Inducible recombination and cell targeting of Nf1 inactivation in NSCs at the clonal level using Nestin-CreERT2 mice.

(a) Injection timeline and paradigm for clonal analysis using NestinCreERT2-based cell targeting. (b) Cumulative distribution plot of cell number of GFP+ clones for those containing OPCs in Nf1Nestin animals (solid circle) and those in controlNestin animals (open circle) at 1 mpi. Each symbol represents data from one clone. *p < 0.01, two-sample Kolmogorov–Smirnov test. (c) Clone at 1 mpi in Nf1Nestin animal with Prox1+ newborn dentate granule neurons (N1, N2) ectopically migrated into the molecular layer (ML) of the dentate gyrus. ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone. Scale bar: 10 μm.

Supplementary Figure 3 Clonal lineage tracing of RGLs upon conditional Nf1 inactivation using Gli1CreERT2-based cell targeting.

(a) Injection timeline and paradigm for clonal analysis using Gli1CreERT2-based cell targeting for adult mice. (b) A tri-lineage clone at 1 mpi in Nf1Gli1 animal with lost or differentiated RGL, astrocytes (open arrowheads), OPCs (closed arrowheads), and mature newborn neurons. Right: high magnification confocal image of boxed region denoting NG2+ OPC. Scale bars: 50 μm and 10 μm (right). (c) A clone at 1 mpi in controlGli1 animal with a maintained RGL (boxed) and mature newborn neurons. Right: maintained nestin+ RGL. Scale bar: 10 μm. See Supplementary Table 3 for number of hemispheres examined under different conditions.

Supplementary Figure 4 Models of adult NSC fate regulation.

Under normal conditions, endogenous RGLs in the adult mouse dentate gyrus are bi-potent and generate only neurons and astrocytes in vivo. NF1 suppresses the oligodendrocytic lineage potential, which can be revealed by removal of NF1.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1–4 (PDF 953 kb)

Supplementary Methods Checklist (PDF 350 kb)

3D rendering and fly-through of reconstructed 2 mpi Nf1Nestin clone shown in Figure 2a.

Four representative OPCs are labeled in addition to the mother RGL. OPC, oligodendrocyte progenitor cell; RGL, radial glia-like cell (MOV 11862 kb)

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Sun, G., Zhou, Y., Ito, S. et al. Latent tri-lineage potential of adult hippocampal neural stem cells revealed by Nf1 inactivation. Nat Neurosci 18, 1722–1724 (2015). https://doi.org/10.1038/nn.4159

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