A Possible Role for the High Mobility Group Box Transcription Factor Tcf-4 in Vertebrate Gut Epithelial Cell Differentiation

YoungJoo Lee,Ramesh A. Shivdasani,Bethany Swencki,Sarah Shoichet

doi:10.1074/jbc.274.3.1566

YoungJoo Lee, Ramesh A. Shivdasani + Show 2 more

Open Access

https://doi.org/10.1074/jbc.274.3.1566

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Abstract

The Wingless (Wg)/Wnt signaling pathway activates High Mobility Group (HMG)-box transcription factors of the T-cell Factor (Tcf)/Lymphoid Enhancer Factor (LEF) subfamily and mediates diverse functions in development, possibly including endoderm and gut differentiation. Determinants of tissue specificity in the response to Wg/Wnt signaling remain unknown. We have identified Tcf-4 as the predominant Tcf/LEF factor in the developing mouse gut. During fetal development, Tcf-4 mRNA expression is restricted to gut epithelium and specific regions of the brain, the thalamus and roof of the midbrain. In adults, expression is widespread, with highest levels observed in the liver, an endodermally derived organ, and persists in the gastrointestinal tract. Murine Tcf-4 has multiple RNA splice variants with consequently significant heterogeneity in sequences 3' to the HMG box. Microinjection of mRNA or plasmid DNA encoding Tcf-4 into Xenopus embryos results in ectopic expression of molecular markers of endoderm and differentiated gut epithelium in isolated animal cap explants. Taken together, these findings point to a potentially important function for Tcf-4 in development of the vertebrate gastrointestinal tract.

Highlights

The Wingless (Wg)1 /Wnt signaling pathway mediates essential aspects of early development and has been elucidated through a combination of genetic and biochemical studies in several species [1]
The correspondence may, be more complicated in vertebrates, which have multiple T-cell Factor (Tcf)/Lymphoid Enhancer Factor (LEF)-related proteins with varying patterns of expression in embryos and adults. Both Tcf-1 and LEF-1 were originally identified through studies in lymphocytes, where their expression is restricted in adult mice (18 –20); during fetal development, their expression is wide and largely overlapping [21, 22]
Development of the gut has long been recognized to depend upon such inductive interactions but Tcf-1 and LEF-1 are not expressed in this organ and absence of either gene does not lead to obvious gut anomalies

Summary

The abbreviations used are

Wingless; HMG, High Mobility Group; Tcf, T-cell factor; LEF, Lymphoid Enhancer Factor; IFABP, intestinal fatty acid binding protein; PCR, polymerase chain reaction; ED, embryonic day; UTR, untranslated region; BCIP, 5-bromo-4-chloro3-indolyl phosphate. A fraction of colorectal tumors with intact APC harbor activating mutations in the ␤-catenin gene [15], and at least one Tcf/LEF protein, human (h) Tcf-4, is commonly expressed in colon cancer cell lines and mediates transcriptional activation therein [16] The sum of these observations strongly implicates ␤-catenin and Tcf/LEF family proteins in normal gut development and in the pathogenesis of gastrointestinal tumors. Ectopic expression of one of these mTcf-4 mRNA isoforms in Xenopus embryos induces expression of gastrointestinal epithelial markers in isolated animal cap explants These observations point to a possibly important function for Tcf-4 in differentiation of the gastrointestinal epithelium and vertebrate gut development

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION