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. 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.
Division of Pediatric Urology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. joo-seop.park@cchmc.org
Joo-Seop
JS
Park
Wenxiu
W
Ma
Lori L
LL
O'Brien
Eunah
E
Chung
Jin-Jin
JJ
Guo
Jr-Gang
JG
Cheng
M Todd
MT
Valerius
Jill A
JA
McMahon
Wing Hung
WH
Wong
Andrew P
AP
McMahon
D000818:Animals; D002478:Cells, Cultured; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009399:Nephrons / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D018398:Homeodomain Proteins; C497420:Six2 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin