Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation

Abstract

Stem cells persist throughout life by self-renewing in numerous tissues including the central1 and peripheral2 nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects3. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: CNS stem cells and gut neural crest stem cells (NCSCs) require Bmi-1 to self-renew normally.
Figure 2: Bmi-1 deficiency reduces proliferation but does not increase cell death in CNS stem cell colonies. P0 SVZ cells were dissociated and plated in adherent cultures, and the number of cells per colony was counted after 4, 7 and 14 d (a).
Figure 3: p16Ink4a negatively regulates the self-renewal of CNS stem cells and gut NCSCs in culture.
Figure 4: Restricted neural progenitors from the CNS and PNS proliferate normally in the absence of Bmi-1. E14 telencephalon cells or P0 or P30 SVZ cells were dissociated and cultured at clonal density under adherent conditions.

References

  1. Morshead, C. M., Craig, C. G. & van der Kooy, D. In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development 125, 2251–2261 (1998)

    CAS  PubMed  Google Scholar 

  2. Kruger, G. M. et al. Neural crest stem cells persist in the adult gut but undergo perinatal changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35, 657–669 (2002)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. van der Lugt, N. M. T. et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 8, 757–769 (1994)

    CAS  Article  PubMed  Google Scholar 

  4. Haupt, Y., Bath, M. L., Harris, A. W. & Adams, J. M. BMI-1 transgene induces lymphomas and collaborates with Myc in tumorigenesis. Oncogene 8, 3161–3164 (1993)

    CAS  PubMed  Google Scholar 

  5. Alkema, M. J., Jacobs, H., van Lohuizen, M. & Berns, A. Perturbation of B and T cell development and predisposition to lymphomagenesis in Eu-Bmi1 transgenic mice require the Bmi1 RING finger. Oncogene 15, 899–910 (1997)

    CAS  Article  PubMed  Google Scholar 

  6. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukemic stem cells. Nature 423, 255–260 (2003)

    ADS  CAS  Article  PubMed  Google Scholar 

  7. Park, I.-K. et al. Bmi-1 is required for the maintenance of adult self-renewing hematopoietic stem cells. Nature 423, 302–305 (2003)

    ADS  CAS  Article  PubMed  Google Scholar 

  8. Davis, A. & Temple, S. A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372, 263–266 (1994)

    ADS  CAS  Article  PubMed  Google Scholar 

  9. Bixby, S., Kruger, G. M., Mosher, J. T., Joseph, N. M. & Morrison, S. J. Cell-intrinsic differences between neural stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity. Neuron 35, 643–656 (2002)

    CAS  Article  PubMed  Google Scholar 

  10. Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999)

    ADS  CAS  Article  PubMed  Google Scholar 

  11. Itahana, K. et al. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell. Biol. 23, 389–401 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Jacobs, J. J. L. et al. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers. Nature Genet. 26, 291–298 (2000)

    CAS  Article  PubMed  Google Scholar 

  13. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  14. Lowe, S. W. & Sherr, C. J. Tumor suppression by Ink4a–Arf: progress and puzzles. Curr. Opin. Genet. Dev. 13, 77–83 (2003)

    CAS  Article  PubMed  Google Scholar 

  15. Zindy, F., Quelle, D. E., Roussel, M. F. & Sherr, C. J. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203–211 (1997)

    CAS  Article  PubMed  Google Scholar 

  16. Rietze, R. L. et al. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412, 736–739 (2001)

    ADS  CAS  Article  PubMed  Google Scholar 

  17. Capela, A. & Temple, S. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35, 865–875 (2002)

    Article  PubMed  Google Scholar 

  18. Shah, N. M., Groves, A. & Anderson, D. J. Alternative neural crest cell fates are instructively promoted by TGFβ superfamily members. Cell 85, 331–343 (1996)

    CAS  Article  PubMed  Google Scholar 

  19. Morrison, S. J., White, P. M., Zock, C. & Anderson, D. J. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell 96, 737–749 (1999)

    CAS  Article  PubMed  Google Scholar 

  20. Shah, N. M., Marchionni, M. A., Isaacs, I., Stroobant, P. W. & Anderson, D. J. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 77, 349–360 (1994)

    CAS  Article  PubMed  Google Scholar 

  21. Bunker, C. A. & Kingston, R. E. Transcriptional repression by Drosophila and mammalian polycomb group proteins in transfected mammalian cells. Mol. Cell. Biol. 14, 1721–1732 (1994)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Jacobs, J. J. L. & van Lohuizen, M. Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim. Biophys. Acta 1602, 151–161 (2002)

    CAS  PubMed  Google Scholar 

  23. Alkema, M. J., van der Lugt, N. M. T., Bobeldijk, R. C., Berns, A. & van Lohuizen, M. Transformation of axial skeleton due to overexpression of bmi-1 in transgenic mice. Nature 374, 724–727 (1995)

    ADS  CAS  Article  PubMed  Google Scholar 

  24. van der Lugt, N. M. T., Alkema, M. J., Berns, A. & Deschamps, J. The Polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression. Mech. Dev. 58, 153–164 (1996)

    CAS  Article  PubMed  Google Scholar 

  25. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000)

    ADS  CAS  Article  PubMed  Google Scholar 

  26. Stritt, T. N. et al. The anticoagulation factor protein S and its relative Gas6, are ligands for the Tyro3/Axl family of receptor tyrosine kinases. Cell 80, 661–670 (1995)

    Article  Google Scholar 

  27. Lois, C. & Alvarez-Buylla, A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc. Natl Acad. Sci. USA 90, 2074–2077 (1993)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Kukuruga, A. M. Deslaurier, M. Kiel and the University of Michigan Flow-Cytometry Core Facility (supported by University of Michigan Comprehensive Cancer and Multipurpose Arthritis Center NIH grants); D. Qian for mouse breeding; D. Misek, R. Koenig and R. Kuick for microarray analysis; E. Smith in the Hybridoma Core Facility (supported through the Michigan Diabetes Research and Training Center, and the Rheumatic Disease Center); M. van Lohuizen for the Bmi1-/- mice; and R. DePinho and D. Scadden for the p16-/- mice. This work was supported by the NIH, the Searle Scholars Program and the Howard Hughes Medical Institute. A.V.M. was supported by a University of Michigan MSTP training grant. R.P. was the recipient of a postdoctoral fellowship from the Spanish Ministry of Science and Technology.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sean J. Morrison.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Molofsky, A., Pardal, R., Iwashita, T. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003). https://doi.org/10.1038/nature02060

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02060

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing