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

Joo Seop Park; Wenxiu Ma; Lori L. O'Brien; Eunah Chung; Jin Jin Guo; Jr Gang Cheng; M. Todd Valerius; Jill A. McMahon; Wing Hung Wong; Andrew P. McMahon

doi:10.1016/j.devcel.2012.07.008

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

Joo Seop Park^*, Wenxiu Ma, Lori L. O'Brien, Eunah Chung, Jin Jin Guo, Jr Gang Cheng, M. Todd Valerius, Jill A. McMahon, Wing Hung Wong, Andrew P. McMahon

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

184 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	637-651
Number of pages	15
Journal	Developmental Cell
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.devcel.2012.07.008
State	Published - Sep 11 2012

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Molecular Biology
Cell Biology
Developmental Biology

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10.1016/j.devcel.2012.07.008

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

abstract = "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.",

author = "Park, {Joo Seop} and Wenxiu Ma and O'Brien, {Lori L.} and Eunah Chung and Guo, {Jin Jin} and Cheng, {Jr Gang} and Valerius, {M. Todd} and McMahon, {Jill A.} and Wong, {Wing Hung} and McMahon, {Andrew P.}",

note = "Funding Information: We thank Brian Tilton, Patricia Rogers, Christian Daly, and Jennifer Couget for their technical support and members of the HSCI Genome Modification Facility for transgenic studies. Work in A.P.M.'s laboratory was supported by a grant from the National Institutes of Health (NIH) (R37 DK054364). J.-S.P. was supported by research fellowships from the National Kidney Foundation and Charles A. King Trust, Bank of America, Co-Trustee (Boston, MA, USA). L.L.O. was supported by a Ruth L. Kirschstein postdoctoral research fellowship from the NIH/NIDDK (F32 DK085959). Work by W.M. and W.H.W. was supported by NIH grants (R01 HG005717 and R01 HG003903). ",

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AU - Park, Joo Seop

AU - Ma, Wenxiu

AU - O'Brien, Lori L.

AU - Chung, Eunah

AU - Guo, Jin Jin

AU - Cheng, Jr Gang

AU - Valerius, M. Todd

AU - McMahon, Jill A.

AU - Wong, Wing Hung

AU - McMahon, Andrew P.

N1 - Funding Information: We thank Brian Tilton, Patricia Rogers, Christian Daly, and Jennifer Couget for their technical support and members of the HSCI Genome Modification Facility for transgenic studies. Work in A.P.M.'s laboratory was supported by a grant from the National Institutes of Health (NIH) (R37 DK054364). J.-S.P. was supported by research fellowships from the National Kidney Foundation and Charles A. King Trust, Bank of America, Co-Trustee (Boston, MA, USA). L.L.O. was supported by a Ruth L. Kirschstein postdoctoral research fellowship from the NIH/NIDDK (F32 DK085959). Work by W.M. and W.H.W. was supported by NIH grants (R01 HG005717 and R01 HG003903).

PY - 2012/9/11

Y1 - 2012/9/11

N2 - 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.

AB - 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.

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

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