Disparate levels of beta-catenin activity determine nephron progenitor cell fate

Ramalingam, Harini; Fessler, Alicia R.; Das, Aditi; Valerius, M. Todd; Basta, Jeannine; Robbins, Lynn W.; Brown, Aaron C.; Oxburgh, Leif; McMahon, Andrew P.; Rauchman, Michael; Carroll, Thomas J.

doi:10.1016/j.ydbio.2018.04.020

Cited by 41 publications

(50 citation statements)

References 36 publications

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“…By contrast, Six2:Cre and Wt1:CreER T2 induced deletions did not interfere with stromal Rspo3 expression, which bestowed sufficient b-catenin signalling in progenitors to permit survival. This hypothesis is compatible with a model in which low and high levels of b-catenin signalling regulates Class II and Class I target genes, respectively 10 . However, the concept of lower b-catenin signalling in uncommitted progenitors seems contradictory considering that they are exposed to higher levels of Rspondins (RSPO1+RSPO3), when compared to cells that engage in MET (only RSPO1).…”

Section: Discussionsupporting

confidence: 87%

“…Class I genes such as Wnt4 that depend on strong b-catenin activation and are highly expressed in pretubular aggregates 5,10 . In situ hybridisation (Ish) analysis revealed that loss of R-spondins did not impact Wnt9b expression ( Fig.…”

Section: Rspo1 and Rspo3 Are Required For Mesenchyme-to-epithelial Trmentioning

confidence: 99%

“…However, canonical WNT signalling is also required for MET 6 and transient activation of b-catenin in isolated progenitors induces epithelialisation 7,8,9 . How the balance between progenitor proliferation and differentiation is achieved is not well understood, but experimental evidence suggests that progenitor proliferation requires low levels of b-catenin activity, whereas genes that are involved in MET are activated in the presence of a strong canonical b-catenin signal 10 . In the context of nephrogenesis, a strong b-catenin response appears to rely on the activation of canonical BMP/SMAD pathway, as progenitor cells leaving the niche are positive for pSMAD and deletion of Bmp7 interferes with MET 11 .…”

Section: Introductionmentioning

confidence: 99%

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Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

Vidal

Gregoire

Szenker‐Ravi

et al. 2019

Preprint

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During kidney development, WNT/β-catenin signalling has to be tightly controlled to ensure proliferation and differentiation of renal stem cells. Here we show that the two signalling molecules RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/β-catenin signalling and their genetic deletion leads to a rapid decline of renal progenitors. By contrast, tissue specific deletion in cap mesenchymal cells abolishes mesenchyme to epithelial transition (MET) that is linked to a loss of Bmp7 expression, absence of SMAD1/5 phosphorylation and a concomitant failure to activate Lef1, Fgf8 and Wnt4, thus explaining the observed phenotype on a molecular level. Surprisingly, the full knockout of LGR4/5/6, the cognate receptors of Rspondins, only mildly affects progenitor numbers, but does not interfere with MET. Taken together our data demonstrate key roles for R-spondins in permitting stem cell maintenance and differentiation and reveal Lgr-dependent and independent functions for these ligands during kidney formation.

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Section: Discussionsupporting

confidence: 87%

Section: Rspo1 and Rspo3 Are Required For Mesenchyme-to-epithelial Trmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

Vidal

Gregoire

Szenker‐Ravi

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Recently, work in cells derived from E10.5 mesonephric mesenchyme identified a role for Rspo1, Lrp6 and Fzd5 in enabling Wnt9b responsiveness as cells transitioned from the intermediate mesoderm to the metanephric mesenchyme identity (Dickinson et al, 2019). It was further demonstrated that low signaling input promotes selfrenewal and high signaling input promotes differentiation (Ramalingam et al, 2018). Our findings explain how Wnt9b signal strength varies to control both decisions, changing over time: a cell intrinsic and progressive increase in translation leads to increased stability (more Rspo, Lrp, Lgr proteins) and clustering (via Tmem59) of Wnt/FZD complexes.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Changes in the Progenitor Translatome Coordinated in part byTsc1Increase Perception of Signaling Inputs to End Nephrogenesis

Brunskill

Jarmas

Chaturvedi

et al. 2020

Preprint

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Mammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that in young niches, cellular Wnt agonists are poorly translated, Fgf20 levels are high and R-spondin levels are low, resulting in a pro self-renewal environment. By contrast, older niches are low in Fgf20 and high in R-spondin, with increased cellular translation of Wnt agonists, including the signalosome-promoting Tmem59. This suggests a hypothesis that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving differentiation. We show Tsc1 hemizygosity differentially promoted translation of Wnt antagonists over agonists, expanding a transitional (Six2+, Cited1+, Wnt4+) state and delaying the tipping point. As predicted by these findings, reducing Rspo3 dosage in nephron progenitors or Tmem59 globally increased nephron numbers in vivo.

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“…4,5 Studies in mice have shown that Osr1, Six2, Wnt and Wt1 are required to maintain renal progenitor cells during kidney organogenesis. 6,7,8,9,10,11 Additionally, signalling pathways such as Wnt, Fgf, Tgfβ and Notch play major roles in renal stem cell maintenance and differentiation. 12,13,14,15 The transcription factor, Odd-skipped related 1 (Osr1), is an early marker specific for the intermediate mesenchyme (IM); knockout mice lack renal structures due to the failure to form the IM.…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Molecular Portrait of Human Urine-derived Renal Progenitor Cells

Rahman

Wruck

Spitzhorn

et al. 2019

Preprint

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Human urine is a non-invasive source of stem cells with regeneration potential. Here, we investigated the cellular and molecular identities, and the gene regulation driving self-renewal and differentiation of these cells in vitro. These cells express pluripotency-associated markers enabling easy reprogramming. Based on the expression of renal associated genes, proteins and functionality, we refer to these cells as urine derived renal progenitor cells-UdRPCs. CHIR99021-induced differentiation of UdRPCs activated WNT-related genes-AXIN2, JUN and NKD1. Protein interaction network identified JUN as a putative regulator of differentiation whereas self-renewal is maintained by FGF2-driven TGFβ-SMAD2/3. Our data will enhance understanding of the molecular identities of UdRPCs, and enable the generation of renal disease models in vitro and eventually kidney-associated regenerative therapies.3 Abstract Background Human urine is now recognised as a non-invasive source of stem cells with regeneration potential. These cells are mesenchymal stem cells but their detailed molecular and cellular identities are poorly defined. Furthermore, unlike the mouse, the gene regulatory network driving self-renewal and differentiation into functional renal cells in vitro remain unresolved. MethodsWe isolated urine stem cells from 10 individuals from both genders and distinct ages, characterized them as renal progenitor cells and explored the gene regulatory network sustaining self-renewal. ResultsThese cells express pluripotency-associated proteins-TRA-1-60, TRA-1-81, SSEA4, C-KIT and CD133. Expression of pluripotency-associated proteins enabled rapid reprogramming into iPSCs using episomal-based plasmids without pathway perturbations. Transcriptome analysis revealed expression of a plethora of nephrogenesis-related genes such as SIX2, OSR1, CITED1, NPHS2, NPHS1, PAX2, SALL1, AQP2, EYA1, SLC12A1 and UMOD. As expected, the cells transport Albumin by endocytosis. Based on this, we refer to these cells as urine derived renal progenitor cells-UdRPCs. Associated GO-term analysis of UdRPCs and UdRPC-iPSCs underlined their renal identity and functionality. Upon differentiation by WNT activation using the GSK3β-inhibitor (CHIR99021), transcriptome and KEGG pathway analysis revealed upregulation of WNT-associated genes-AXIN2, JUN and NKD1. Protein interaction network identified JUN-a downstream target of the WNT pathway in association with STAT3, ATF2 and MAPK1 as a putative regulator of self-renewal and differentiation in UdRPCs. Furthermore, like pluripotent stem cells, self-renewal is maintained by FGF2-driven TGFβ-SMAD2/3 pathway.Conclusion This in vitro model and the data presented should lay the foundation for studying nephrogenesis in man.

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Disparate levels of beta-catenin activity determine nephron progenitor cell fate

Cited by 41 publications

References 36 publications

Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

Paracrine and autocrine R-spondin signalling is essential for the maintenance and differentiation of renal stem cells

Age-Dependent Changes in the Progenitor Translatome Coordinated in part byTsc1Increase Perception of Signaling Inputs to End Nephrogenesis

A Comprehensive Molecular Portrait of Human Urine-derived Renal Progenitor Cells

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