Myb Controls Intestinal Stem Cell Genes and Self-Renewal§

Authors

  • Dane Cheasley,

    1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  • Lloyd Pereira,

    1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    2. Department of Pathology University of Melbourne, Melbourne, Victoria, Australia
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  • Sally Lightowler,

    1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    2. Department of Pathology University of Melbourne, Melbourne, Victoria, Australia
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  • Elizabeth Vincan,

    1. Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria, Australia
    2. Victorian Infectious Diseases Reference Laboratories, Melbourne, Victoria, Australia
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  • Jordane Malaterre,

    1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    2. Department of Pathology University of Melbourne, Melbourne, Victoria, Australia
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  • Robert G. Ramsay

    Corresponding author
    1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    2. Department of Pathology University of Melbourne, Melbourne, Victoria, Australia
    • Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, 3002 Victoria, Australia
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    • Telephone: 613-9656-1863; Fax: 613-9656-1411


  • Author contributions: D.C.: collection and assembly of data, manuscript writing, and data analysis and interpretation; L.P. and E.V.: collection and assembly of data and data analysis and interpretation; S.L.: collection and assembly of data; J.M.: collection and assembly of data, conception and design, manuscript writing, and data analysis and interpretation; R.R.: conception and design, financial support, manuscript writing, final approval of manuscript, and data analysis and interpretation.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS October 13, 2011.

Abstract

Rapid advances have been made in the understanding of how the highly proliferative gastrointestinal tract epithelium is regulated under homeostasis and disease. The identification of putative intestinal stem cell (ISC) genes and the ability to culture ISC capable of generating all four lineages plus the architecture of small intestinal (SI) crypts has been transformative. Here, we show that transcription factor Myb governs ISC gene expression, particularly Lgr5. Lgr5 is associated with cells that have the capacity to generate all cell lineages in SI organoid cultures and colorectal cancer cells, which overexpress Myb. Furthermore, Wnt signaling and Myb cooperate in maximal Lgr5 promoter activation while hypomorphic Myb (plt4/plt4) mice have decreased Lgr5 expression. After ionizing radiation (IR), ISC genes are elevated; but in plt4/plt4 mice, this response is substantially subdued. ISC genes bmi-1 and olfm4 are expressed at subnormal levels in plt4/plt4 mice, and bmi-1 is induced with IR to half the level in mutant mice. dcamkl-1 and olfm4 failed to recover after IR in both wild-type (wt) and mutant mice. Although not considered as an ISC gene, cyclinE1 is nevertheless used to assist cells in the emergence from a quiescent state (an expectation of ISC following IR) and is overexpressed after IR in wt mice but does not change from a very low base in plt4/plt4 mice. Self-renewal assays using organoid cultures and inducible Myb knockout studies further highlighted the dependence of ISC on Myb consistent with role in other stem cell-containing tissues. Stem Cells 2011;29:2042–2050.

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