Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism

BackgroundEya1 is a critical regulator of nephron progenitor cell specification and interacts with Six2 to promote NPC self-renewal. Haploinsufficiency of these genes causes kidney hypoplasia. However, how the Eya1-centered network operates remains unknown.MethodsWe engineered a 2×HA-3×Flag-Eya1 knock-in mouse line and performed coimmunoprecipitation with anti-HA or -Flag to precipitate the multitagged-Eya1 and its associated proteins. Loss-of-function, transcriptome profiling, and genome-wide binding analyses for Eya1's interacting chromatin-remodeling ATPase Brg1 were carried out. We assayed the activity of the cis-regulatory elements co-occupied by Brg1/Six2 in vivo.ResultsEya1 and Six2 interact with the Brg1-based SWI/SNF complex during kidney development. Knockout of Brg1 results in failure of metanephric mesenchyme formation and depletion of nephron progenitors, which has been linked to loss of Eya1 expression. Transcriptional profiling shows conspicuous downregulation of important regulators for nephrogenesis in Brg1-deficient cells, including Lin28, Pbx1, and Dchs1-Fat4 signaling, but upregulation of podocyte lineage, oncogenic, and cell death–inducing genes, many of which Brg1 targets. Genome-wide binding analysis identifies Brg1 occupancy to a distal enhancer of Eya1 that drives nephron progenitor–specific expression. We demonstrate that Brg1 enrichment to two distal intronic enhancers of Pbx1 and a proximal promoter region of Mycn requires Six2 activity and that these Brg1/Six2-bound enhancers govern nephron progenitor–specific expression in response to Six2 activity.ConclusionsOur results reveal an essential role for Brg1, its downstream pathways, and its interaction with Eya1-Six2 in mediating the fine balance among the self-renewal, differentiation, and survival of nephron progenitors.

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Promotion of nephron progenitor cell self-renewal

Nature Reviews Nephrology ◽

10.1038/nrneph.2015.213 ◽

2015 ◽

Vol 12 (2) ◽

pp. 62-62

Author(s):

Jessica K. Edwards

Keyword(s):

Progenitor Cell ◽

Self Renewal ◽

Nephron Progenitor

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Nephron progenitor commitment is a stochastic process influenced by cell migration

eLife ◽

10.7554/elife.41156 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 12

Author(s):

Kynan T Lawlor ◽

Luke Zappia ◽

James Lefevre ◽

Joo-Seop Park ◽

Nicholas A Hamilton ◽

...

Keyword(s):

Cell Migration ◽

Progenitor Cell ◽

Computational Modelling ◽

Rna Seq ◽

Self Renewal ◽

Tissue Microenvironment ◽

Nephron Progenitors ◽

Nephron Progenitor ◽

Robust Regulation ◽

Over Time

Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. Here, we examine how progenitor cell migration impacts regionally induced commitment within the nephrogenic niche in mice. We identify a subset of cells that express Wnt4, an early marker of nephron commitment, but migrate back into the progenitor population where they accumulate over time. Single cell RNA-seq and computational modelling of returning cells reveals that nephron progenitors can traverse the transcriptional hierarchy between self-renewal and commitment in either direction. This plasticity may enable robust regulation of nephrogenesis as niches remodel and grow during organogenesis.

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Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment

eLife ◽

10.7554/elife.40392 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 11

Author(s):

Lori L O'Brien ◽

Alexander N Combes ◽

Kieran M Short ◽

Nils O Lindström ◽

Peter H Whitney ◽

...

Keyword(s):

Gene Expression ◽

Progenitor Cell ◽

Live Imaging ◽

Rna Seq ◽

Self Renewal ◽

Mammalian Kidney ◽

Nephron Endowment ◽

Nephron Progenitors ◽

Cell Organization ◽

Nephron Progenitor

A normal endowment of nephrons in the mammalian kidney requires a balance of nephron progenitor self-renewal and differentiation throughout development. Here, we provide evidence for a novel action of ureteric branch tip-derived Wnt11 in progenitor cell organization and interactions within the nephrogenic niche, ultimately determining nephron endowment. In Wnt11 mutants, nephron progenitors dispersed from their restricted niche, intermixing with interstitial progenitors. Nephron progenitor differentiation was accelerated, kidneys were significantly smaller, and the nephron progenitor pool was prematurely exhausted, halving the final nephron count. Interestingly, RNA-seq revealed no significant differences in gene expression. Live imaging of nephron progenitors showed that in the absence of Wnt11 they lose stable attachments to the ureteric branch tips, continuously detaching and reattaching. Further, the polarized distribution of several markers within nephron progenitors is disrupted. Together these data highlight the importance of Wnt11 signaling in directing nephron progenitor behavior which determines a normal nephrogenic program.

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Faculty Opinions recommendation of Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718238823.793489824 ◽

2014 ◽

Author(s):

Simon Hayward

Keyword(s):

Bisphenol A ◽

Progenitor Cell ◽

Human Prostate ◽

Self Renewal ◽

Prostate Epithelium

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Faculty Opinions recommendation of Generation of interspecies limited chimeric nephrons using a conditional nephron progenitor cell replacement system.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732155029.793556843 ◽

2019 ◽

Author(s):

Masaomi Nangaku ◽

Sho Hasegawa

Keyword(s):

Progenitor Cell ◽

Cell Replacement ◽

Replacement System ◽

Nephron Progenitor

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Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1800184115 ◽

2018 ◽

Vol 115 (12) ◽

pp. E2725-E2733 ◽

Cited By ~ 13

Author(s):

Yulong Cai ◽

Xiaotong Tang ◽

Xi Chen ◽

Xin Li ◽

Ying Wang ◽

...

Keyword(s):

Dentate Gyrus ◽

Progenitor Cells ◽

Progenitor Cell ◽

Neural Progenitor Cells ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Liver X Receptor ◽

Self Renewal ◽

Spectrum Disorders ◽

Deficient Mice

The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRβ in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRβ-null mice. In addition, LXRβ deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRβ in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRβ-deficient mice.

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Nfatc1’s Role in Mammary Epithelial Morphogenesis and Basal Stem/progenitor Cell Self-renewal

Journal of Mammary Gland Biology and Neoplasia ◽

10.1007/s10911-021-09502-6 ◽

2021 ◽

Author(s):

Melissa McNeil ◽

Yingying Han ◽

Peng Sun ◽

Kazuhide Watanabe ◽

Jun Jiang ◽

...

Keyword(s):

Stem Cell ◽

Mammary Gland ◽

Progenitor Cell ◽

Cell Function ◽

Cell Activity ◽

Basal Layer ◽

Mammary Epithelial ◽

Epithelial Morphogenesis ◽

Small Subset ◽

Self Renewal

AbstractMammary gland is an outstanding system to study the regulatory mechanisms governing adult epithelial stem cell activity. Stem cells in the basal layer of the mammary gland fuel the morphogenesis and regeneration of a complex epithelial network during development and upon transplantation. The self-renewal of basal stem/progenitor cells is subjected to regulation by both cell-intrinsic and extrinsic mechanisms. Nfatc1 is a transcription factor that regulates breast tumorigenesis and metastasis, but its role in mammary epithelial development and stem cell function has not been investigated. Here we show that Nfatc1 is expressed in a small subset of mammary basal epithelial cells and its epithelial-specific deletion results in mild defects in side branching and basal-luminal cell balance. Moreover, Nfatc1-deficient basal cells exhibit reduced colony forming ability in vitro and somewhat compromised regenerative potential upon transplantation. Thus, our study provides evidence for a detectable yet non-essential role of Nfatc1 in mammary epithelial morphogenesis and basal stem/progenitor cell self-renewal.

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