Six2 and Wnt Regulate Self-Renewal and Commitment of Nephron Progenitors through Shared Gene Regulatory Networks

A balance between Six2-dependent self-renewal and canonical Wnt signaling-directed commitment regulates mammalian nephrogenesis. Intersectional studies using chromatin immunoprecipitation and transcriptional profiling identified direct target genes shared by each pathway within nephron progenitors....

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Bibliographic Details
Published in:Developmental cell 2012-09, Vol.23 (3), p.637-651
Main Authors: Park, Joo-Seop, Ma, Wenxiu, O'Brien, Lori L., Chung, Eunah, Guo, Jin-Jin, Cheng, Jr-Gang, Valerius, M. Todd, McMahon, Jill A., Wong, Wing Hung, McMahon, Andrew P.
Format: Article
Language:English
Subjects:
Animals
beta Catenin - genetics
beta Catenin - metabolism
Biological and medical sciences
catenin
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
Cells, Cultured
Chromatin
DNA
Fibroblast growth factor 8
Fundamental and applied biological sciences. Psychology
Gene Regulatory Networks
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Immunoprecipitation
Kidney
LEF protein
Mice
Mice, Transgenic
Molecular and cellular biology
Nephrons
Nephrons - cytology
Nephrons - embryology
Nephrons - metabolism
Signal transduction
Stem cells
Stem Cells - cytology
Stem Cells - metabolism
Tcf protein
Transcription
Transcription Factors - genetics
Transcription Factors - metabolism
Wnt protein
Wnt Signaling Pathway
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Summary:A balance between Six2-dependent self-renewal and canonical Wnt signaling-directed commitment regulates mammalian nephrogenesis. Intersectional studies using chromatin immunoprecipitation and transcriptional profiling identified direct target genes shared by each pathway within nephron progenitors. Wnt4 and Fgf8 are essential for progenitor commitment; cis-regulatory modules flanking each gene are cobound by Six2 and β-catenin and are dependent on conserved Lef/Tcf binding sites for activity. In vitro and in vivo analyses suggest that Six2 and Lef/Tcf factors form a regulatory complex that promotes progenitor maintenance while entry of β-catenin into this complex promotes nephrogenesis. Alternative transcriptional responses associated with Six2 and β-catenin cobinding events occur through non-Lef/Tcf DNA binding mechanisms, highlighting the regulatory complexity downstream of Wnt signaling in the developing mammalian kidney. ► Identification of gene regulatory networks in nephron progenitors ► Maintenance and commitment pathways integrated at cis-regulatory modules ► Multiple roles for β-catenin complexes in progenitor programs Nephron progenitors must balance Six2-dependent self-renewal with Wnt/β-catenin-directed differentiation. Park et al. performed genome-wide analyses of target genes regulated by Six2 and β-catenin in these cells. Their work identifies key cis-regulatory nodes and defines distinct ways in which these transcriptional regulators interact and coordinate the control of kidney gene expression.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2012.07.008