Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkühn is perturbed by stimulation of Lef-1/β-catenin signaling

Melissa Wong, Joerg Huelsken, Walter Birchmeier, Jeffrey I. Gordon

Research output: Contribution to journalArticle

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Abstract

Studies of chimeric mice have disclosed that the stem cell hierarchy in the small intestinal epithelium is established during formation of its proliferative units (crypts of Lieberkühn). This process involves a selection among several multipotential progenitors so that ultimately only one survives to supply descendants to the fully formed crypt. In this report, we examine the hypothesis that the level of β-catenin (β-cat)-mediated signaling is an important factor regulating this stem cell selection. In the canonical Wnt signaling pathway, β-catenin can partner with Lef-1/Tcf high mobility group (HMG) box transcription factors to control gene expression. Both Lef-1 and Tcf-4 mRNAs are produced in the fetal mouse small intestine. Tcf-4 expression is sustained, whereas Lef-1 levels fall as crypt formation is completed during the first two postnatal weeks. A Tcf-4 gene knockout is known to block intestinal epithelial proliferation in late fetal life. Therefore, to test the hypothesis, we enhanced β-catenin signaling in a chimeric mouse model in which the stem cell selection could be monitored. A fusion protein containing the HMG box domain of Lef-1 linked to the trans-activation domain of β-catenin (Lef-1/β-cat) was constructed to promote direct stimulation of signaling without being retained in the cytoplasm through interactions with E-cadherin and Apc/Axin. Lef-1/β-cat was expressed in 129/Sv embryonic stem cell-derived small intestinal epithelial progenitors present in developing B6-ROSA26↔129/Sv chimeras. Lef-1/β-cat stimulated expression of a known β-catenin target (E-cadherin), suppressed expression of Apc and Axin, and induced apoptosis in 129/Sv but not in neighboring B6-ROSA26 epithelial cells. This apoptotic response was not associated with any detectable changes in cell division within the Lef-1/β-cat-expressing epithelium. By the time crypt development was completed, all 129/Sv epithelial cells were lost. These results indicate that developmental changes in β-catenin-mediated signaling can play an important role in establishing a stem cell hierarchy during crypt morphogenesis.

Original languageEnglish (US)
Pages (from-to)15843-15850
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number18
DOIs
StatePublished - May 3 2002
Externally publishedYes

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Multipotent Stem Cells
Catenins
Stem cells
Morphogenesis
Cats
Wnt Signaling Pathway
Stem Cells
Cadherins
HMG-Box Domains
Epithelial Cells
Gene Knockout Techniques
Stem Cell Factor
Intestinal Mucosa
Embryonic Stem Cells
Gene expression
Cell Division
Small Intestine
Cytoplasm
Transcription Factors
Fusion reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Selection of multipotent stem cells during morphogenesis of small intestinal crypts of Lieberkühn is perturbed by stimulation of Lef-1/β-catenin signaling. / Wong, Melissa; Huelsken, Joerg; Birchmeier, Walter; Gordon, Jeffrey I.

In: Journal of Biological Chemistry, Vol. 277, No. 18, 03.05.2002, p. 15843-15850.

Research output: Contribution to journalArticle

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