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Bmi1 is expressed in vivo in intestinal stem cells

Abstract

Bmi1 plays an essential part in the self-renewal of hematopoietic and neural stem cells. To investigate its role in other adult stem cell populations, we generated a mouse expressing a tamoxifen-inducible Cre from the Bmi1 locus. We found that Bmi1 is expressed in discrete cells located near the bottom of crypts in the small intestine, predominantly four cells above the base of the crypt (+4 position). Over time, these cells proliferate, expand, self-renew and give rise to all the differentiated cell lineages of the small intestine epithelium. The induction of a stable form of β-catenin in these cells was sufficient to rapidly generate adenomas. Moreover, ablation of Bmi1+ cells using a Rosa26 conditional allele, expressing diphtheria toxin, led to crypt loss. These experiments identify Bmi1 as an intestinal stem cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than one molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis.

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Figure 1: Early Bmi1+ lineage detection.
Figure 2: Repopulation kinetics of the Bmi1+ lineage.
Figure 3: Bmi1+ lineage analysis in the small intestine.
Figure 4: Assessment of Bmi1+ lineage after 5 d and after 12 months to evaluate the colocalization with differentiated-cell markers.
Figure 5: Bmi1CreER/+;Ctnnb1Ex3LoxP/+ cross.
Figure 6: Intestinal stem cell ablation.

References

  1. Wagers, A.J. & Weissman, I.L. Plasticity of adult stem cells. Cell 116, 639–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Seaberg, R.M. & van der Kooy, D. Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci. 26, 125–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Ahn, S. & Joyner, A.L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Molofsky, A.V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. van Lohuizen, M. et al. Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging. Cell 65, 737–752 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Valk-Lingbeek, M.E. & Bruggeman, S.W.M. & van Lohuizen, M. Stem cells and cancer: the Polycomb connection. Cell 118, 409–418 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nat. Genet. 39, 157–158 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. van der Lugt, N.M. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Hayashi, S. & McMahon, A.P. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol. 244, 305–318 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Indra, A.K. et al. Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen- inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res. 27, 4324–4327 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Potten, C.S. Radiation, the ideal cytotoxic agent for studying the cell biology of tissues such as the small intestine. Radiat. Res. 161, 123–136 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Bjerknes, M. & Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 116, 7–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Wong, M.H., Stappenbeck, T.S. & Gordon, J.I. Living and commuting in intestinal crypts. Gastroenterology 116, 208–210 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Potten, C.S., Owen, G. & Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J. Cell Sci. 115, 2381–2388 (2002).

    CAS  PubMed  Google Scholar 

  20. Bjerknes, M. & Cheng, H. Gastrointestinal stem cells. II. Intestinal stem cells. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G381–G387 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Bjerknes, M. & Cheng, H. Intestinal epithelial stem cells and progenitors. Methods Enzymol. 419, 337–383 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Wong, M.H., Saam, J.R., Stappenbeck, T.S., Rexer, C.H. & Gordon, J.I. Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection. Proc. Natl. Acad. Sci. USA 97, 12601–12606 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Clarke, M.F. & Fuller, M. Stem cells and cancer: two faces of Eve. Cell 124, 1111–1115 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 18, 5931–5942 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, S., Wu, Y. & Capecchi, M.R. Motoneurons and oligodendrocytes are sequentially generated from neural stem cells but do not appear to share common lineage-restricted progenitors in vivo. Development 133, 581–590 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Akasaka, T. et al. Mice doubly deficient for the Polycomb Group genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiation of Hox gene expression. Development 128, 1587–1597 (2001).

    CAS  PubMed  Google Scholar 

  28. Preston, S.L. et al. Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res. 63, 3819–3825 (2003).

    CAS  PubMed  Google Scholar 

  29. Shih, I.M. et al. Top-down morphogenesis of colorectal tumors. Proc. Natl. Acad. Sci. USA 98, 2640–2645 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Taketo for providing the β-catenin mouse line; A. Sanchez-Alvarado, A. Boulet, L. Carroll, S. Covington, M. Hockin and K. Thomas for critical reading of the manuscript; and the other members of the Capecchi laboratory for sharing discussions and ideas. We gratefully acknowledge efforts by all of the members of our tissue culture and mouse facility, in particular S. Barnett, C. Lenz and J. Tomlin.

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E.S. designed this study, performed the experiments and wrote the paper; M.R.C. designed this study and wrote the paper.

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Correspondence to Mario R Capecchi.

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Supplementary Methods, Supplementary Table 1 and Supplementary Figures 1 and 2 (PDF 307 kb)

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Sangiorgi, E., Capecchi, M. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40, 915–920 (2008). https://doi.org/10.1038/ng.165

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