title: beta-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors.
abstract: In the embryonic kidney, progenitors in the metanephric mesenchyme differentiate into specialized renal epithelia in a defined sequence characterized by the formation of cellular aggregates, conversion into polarized epithelia and segmentation along a proximal-distal axis. This sequence is reiterated throughout renal development to generate nephrons. Here, we identify global transcriptional programs associated with epithelial differentiation utilizing an organ culture model of rat metanephric mesenchymal differentiation, which recapitulates the hallmarks of epithelialization in vivo in a synchronized rather than reiterative fashion. We observe activation of multiple putative targets of beta-catenin/TCF/Lef-dependent transcription coinciding with epithelial differentiation. We show in cultured explants that isolated activation of beta-catenin signaling in epithelial progenitors induces, in a TCF/Lef-dependent manner, a subset of the transcripts associated with epithelialization, including Pax8, cyclin D1 (Ccnd1) and Emx2. This is associated with anti-apoptotic and proliferative effects in epithelial progenitors, whereas cells with impaired TCF/Lef-dependent transcription are progressively depleted from the epithelial lineage. In vivo, TCF/Lef-responsive genes comprise a conserved transcriptional program in differentiating renal epithelial progenitors and beta-catenin-containing transcriptional complexes directly bind to their promoter regions. Thus, beta-catenin/TCF/Lef-mediated transcriptional events control a subset of the differentiation-associated transcriptional program and thereby participate in maintenance, expansion and stage progression of the epithelial lineage.
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. kms2115@columbia.edu
authors: Kai M
authors: KM
authors: Schmidt-Ott
authors: T Nestor H
authors: TN
authors: Masckauchan
authors: Xia
authors: X
authors: Chen
authors: Benjamin J
authors: BJ
authors: Hirsh
authors: Abby
authors: A
authors: Sarkar
authors: Jun
authors: J
authors: Yang
authors: Neal
authors: N
authors: Paragas
authors: Valerie A
authors: VA
authors: Wallace
authors: Daniel
authors: D
authors: Dufort
authors: Paul
authors: P
authors: Pavlidis
authors: Bernd
authors: B
authors: Jagla
authors: Jan
authors: J
authors: Kitajewski
authors: Jonathan
authors: J
authors: Barasch
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D016000:Cluster Analysis; D016384:Consensus Sequence; D004847:Epithelial Cells / Q000166:cytology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000196:embryology*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D051820:TCF Transcription Factors / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051820:TCF Transcription Factors; D051176:beta Catenin