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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.

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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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