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First published online August 10, 2007
doi: 10.1242/10.1242/dev.006544
1 Department of Medicine, Columbia University College of Physicians and
Surgeons, 630 West 168th Street, New York, NY 10032, USA.
2 Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10,
D-13125 Berlin, Germany.
3 Department of Obstetrics and Gynecology, Columbia University College of
Physicians and Surgeons, New York, NY 10032, USA.
4 Molecular Medicine Program, Ottawa Health Research Institute and University of
Ottawa Eye Institute, Ottawa, ON, Canada.
5 Department of Obstetrics and Gynecology, Division of Experimental Medicine,
McGill University Health Center, Royal Victoria Hospital, Montreal, QC,
Canada.
6 Department of Biomedical Informatics, Columbia University College of
Physicians and Surgeons, New York, NY 10032, USA.
* Authors for correspondence (e-mails: kms2115{at}columbia.edu; jmb4{at}columbia.edu)
Accepted 18 June 2007
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 ß-catenin/TCF/Lef-dependent transcription coinciding with epithelial differentiation. We show in cultured explants that isolated activation of ß-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 ß-catenin-containing transcriptional complexes directly bind to their promoter regions. Thus, ß-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.
Key words: Metanephric mesenchyme, Epithelial differentiation, ß-catenin, TCF/Lef-type transcription factors, Neutrophil gelatinase-associated lipocalin, Leukemia inhibitory factor, Wnt4, Emx2, Pax8, Cyclin D1 (Ccnd1), Frzb
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