-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors

INTRODUCTION Development of the metanephric kidney is initiated when the ureteric bud enters the metanephric mesenchyme and induces mesenchymal progenitors to differentiate into renal epithelia. Epithelialization of the metanephric mesenchyme develops in a sequence that is currently defined by morphological criteria and by the expression of signature molecules (Dressler, 2006). Initially, metanephric mesenchymal progenitors organize at the tips of the ureteric bud forming the ‘condensed mesenchyme’. This is followed by translocation relative to the elongating ureteric bud stalk to generate a ‘pretubular aggregate’ characterized by expression of Wnt4 and Pax8 (Stark et al., 1994). Establishment of apical-basal polarity in this aggregate produces the renal vesicle, a structure characterized by the onset of expression of E-cadherin (also known as cadherin 1, Cdh1), a crucial component of epithelial adherens junctions (Barasch et al., 1999; Cho et al., 1998). Segmentation events lead to the formation of the ‘S-shaped’ body, the direct precursor to mature nephrons, which includes a glomerular pole proximally and a tubular pole distally that connects to the tip of the ureteric bud (Dressler, 2006). In vivo, epithelial differentiation of mesenchymal progenitors is dependent on the presence of the ureteric bud. This sequence can be modeled in vitro by application of defined combinations of growth factors to rat metanephric mesenchyme, which we and others have previously identified by protein chromatography from a ureteric bud cell line (Barasch et al., 1996; Barasch et al., 1999; Karavanova et al., 1996; Plisov et al., 2001; Yang et al., 2002a; Yang et al., 2002b). Application of these growth factors results in the highly reproducible and synchronized appearance of segmented tubules that include glomerular-like structures, proximal tubules and distal tubules (Barasch et al., 1999). The molecular events that drive stage transitions in the epithelial lineage are subject to ongoing research. Although extracellular factors from the WNT, transforming growth factor (TGF ), fibroblast growth factor (FGF) and interleukin 6 (IL6) families have been implicated as regulators of different aspects of epithelial differentiation (Barasch et al., 1999; Carroll et al., 2005; Kispert et al., 1998; Oxburgh et al., 2004; Perantoni et al., 1995; Stark et al., 1994), little is known about the transcriptional events involved in these processes. In the current paper, we analyzed genome-wide transcriptional profiles associated with epithelial differentiation using microarray analysis. Activated transcripts included multiple putative target genes of transcription factors of the TCF/Lef family, suggesting that these factors might participate in the control of epithelial differentiation. -catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors