Molecular determinants of WNT9b responsiveness in nephron progenitor cells

Dickinson, Kyle; Hammond, Leah; Karner, Courtney M.; Hastie, Nicholas D.; Carroll, Thomas J.; Goodyer, Paul

doi:10.1371/journal.pone.0215139

Cited by 16 publications

(6 citation statements)

References 53 publications

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“…It has been long-appreciated that a UB-derived Wnt9b canonical signal is required for both maintenance of self-renewal capacity of NPC, as well as for their differentiation 71 , 72 . 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 73 . It was further demonstrated that low signaling input promotes self-renewal and high signaling input promotes differentiation 74 .…”

Section: Discussionmentioning

confidence: 99%

Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis

et al. 2021

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Mammalian nephron endowment is determined by the coordinated cessation of nephrogenesis in independent niches. Here we report that translatome analysis in Tsc1+/− nephron progenitor cells from mice with elevated nephron numbers reveals how differential translation of Wnt antagonists over agonists tips the balance between self-renewal and differentiation. Wnt agonists are poorly translated in young niches, resulting in an environment with low R-spondin and high Fgf20 promoting self-renewal. In older niches we find increased translation of Wnt agonists, including R-spondin and the signalosome-promoting Tmem59, and low Fgf20, promoting differentiation. This suggests that the tipping point for nephron progenitor exit from the niche is controlled by the gradual increase in stability and possibly clustering of Wnt/Fzd complexes in individual cells, enhancing the response to ureteric bud-derived Wnt9b inputs and driving synchronized differentiation. As predicted by these findings, removing one Rspo3 allele in nephron progenitors delays cessation and increases nephron numbers in vivo.

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Section: Discussionmentioning

confidence: 99%

Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis

et al. 2021

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“…26 Thus, we hypothesized that the morphological changes observed in the stromal Tcf21 KO kidney are mediated by disruption in β-catenin signaling. Using the metanephric mesenchyme mouse cell-lines MK3 and M15 27,28 we examined the effect of Tcf21 on Wnt/ β-catenin signaling. Immunostaining for β-catenin in Foxd1CreTcf21 f/f kidneys showed markedly reduced expression in the medullary stroma at E14.5 and E16.5 (Figure 5A, A', B, B').…”

Section: Tcf21 Cooperates With β-Catenin To Promote Wnt Signaling In ...mentioning

confidence: 99%

Stromal Transcription Factor 21 Regulates Development of the Renal Stroma via Interaction with Wnt/β-Catenin Signaling

et al. 2022

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Background: Kidney formation requires coordinated interactions between multiple cell types. Input from the interstitial progenitor cells is implicated in multiple aspects of kidney development. We previously reported that the Transcription Factor 21 (Tcf21) is required for ureteric bud branching. Here, we show that Tcf21 in Foxd1+ interstitial progenitors regulates stromal formation and differentiation via interaction with β-catenin. Methods: We utilized the Foxd1Cre;Tcf21f/f mouse kidney for morphological analysis. We used the mouse clonal mesenchymal cell lines MK3/M15 to study Tcf21 interaction with Wnt/β-catenin. Results: Absence of Tcf21 from Foxd1+ stromal progenitors caused decrease in stromal cell proliferation, leading to marked reduction of the medullary stromal space. Lack of Tcf21 in the Foxd1+ stromal cells also led to defective differentiation of interstitial cells to smooth muscle cells, perivascular pericytes and mesangial cells. Foxd1Cre;Tcf21f/f kidney showed abnormal pattern of the renal vascular tree. The stroma of Foxd1Cre;Tcf21f/f kidney demonstrated marked reduction in β-catenin protein expression compared to wild-type. Tcf21 was bound to β-catenin both upon β-catenin stabilization and at basal state as demonstrated by immunoprecipitation in-vitro. In MK3/M15 metanephric mesenchymal cells, Tcf21 enhanced TCF/LEF promoter activity upon β-catenin stabilization while DNA-binding deficient mutated Tcf21 did not enhance TCF/LEF promoter activity. Kidney explants of Foxd1Cre;Tcf21f/f showed low mRNA expression of stromal Wnt target genes. Treatment of the explants with CHIR, a Wnt ligand mimetic, restored Wnt target gene expression. Here, we also corroborated previous evidence that normal development of the kidney stroma is required for normal development of the Six2+ nephron progenitor cells, loop of Henle, and the collecting ducts. Conclusion: These findings suggest that stromal Tcf21 facilitates medullary stroma development by enhancing Wnt/β-catenin signaling and promotes stromal cell proliferation and differentiation. Stromal Tcf21 is also required for the development of the adjacent nephron epithelia.

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“…How is nephrogenesis then restricted to the branch corner region? Given the complexity of canonical WNT signaling with its many redundant pathway components [29, 39, 49] and the extensive cross-talk of the WNT9b/WNT4/SIX2 core network with other signalling pathways [3, 12], pre-existing differences in WNT responsiveness could, in principle, spatially restrict PTA/RV formation. Also, BMP7 signalling via the mitogen-activated protein kinase (MAPK) pathway maintains progenitors, while SMAD-mediated BMP7 signalling primes progenitors for WNT/ β -catenin mediated differentiation [2, 3].…”

Section: Introductionmentioning

confidence: 99%

Geometric Effects Position Renal Vesicles During Kidney Development

Mederacke

Conrad

Vetter

et al. 2022

Preprint

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During kidney development, reciprocal signalling between the epithelium and the mesenchyme coordinates nephrogenesis with branching morphogenesis of the collecting ducts. The mechanism that positions the renal vesicles, and thus the nephrons, relative to the branching ureteric buds has remained elusive. By combining computational modelling and experiments, we show that geometric effects concentrate the key regulator, WNT9b, at the junctions between parent and daughter branches where renal vesicles emerge, despite its uniform expression in the ureteric epithelium. This curvature effect might be a general paradigm to create non-uniform signalling in development.

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Molecular determinants of WNT9b responsiveness in nephron progenitor cells

Cited by 16 publications

References 53 publications

Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis

Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis

Stromal Transcription Factor 21 Regulates Development of the Renal Stroma via Interaction with Wnt/β-Catenin Signaling

Geometric Effects Position Renal Vesicles During Kidney Development

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