title: Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis.
abstract: Mammalian kidney organogenesis involves reciprocal epithelial-mesenchymal interactions that drive iterative cycles of nephron formation. Recent studies have demonstrated that the Six2 transcription factor acts cell autonomously to maintain nephron progenitor cells, whereas canonical Wnt signaling induces nephron differentiation. How Six2 maintains the nephron progenitor cells against Wnt-directed commitment is not well understood, however. We report here that Six2 is required to maintain expression of Osr1, a homolog of the Drosophila odd-skipped zinc-finger transcription factor, in the undifferentiated cap mesenchyme. Tissue-specific inactivation of Osr1 in the cap mesenchyme caused premature depletion of nephron progenitor cells and severe renal hypoplasia. We show that Osr1 and Six2 act synergistically to prevent premature differentiation of the cap mesenchyme. Furthermore, although both Six2 and Osr1 could form protein interaction complexes with TCF proteins, Osr1, but not Six2, enhances TCF interaction with the Groucho family transcriptional co-repressors. Moreover, we demonstrate that loss of Osr1 results in β-catenin/TCF-mediated ectopic activation of Wnt4 enhancer-driven reporter gene expression in the undifferentiated nephron progenitor cells in vivo. Together, these data indicate that Osr1 plays crucial roles in Six2-dependent maintenance of nephron progenitors during mammalian nephrogenesis by stabilizing TCF-Groucho transcriptional repressor complexes to antagonize Wnt-directed nephrogenic differentiation.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Xu
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Joo-Seop
authors.initials: JS
authors.lastname: Park
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Rulang
authors.initials: R
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009399:Nephrons / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics*; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C121641:Osr1 protein, mouse; C497420:Six2 protein, mouse; D014157:Transcription Factors
keywords: Groucho; Kidney development; Nephron progenitor; Odd-skipped; Osr1; Six2; Wnt signaling