Cross-platform single cell analysis of kidney development shows stromal cells express Gdnf

Magella, Bliss; Adam, Mike; Potter, Andrew; Venkatasubramanian, Meenakshi; Chetal, Kashish; Hay, Stuart; Salomonis, Nathan; Potter, S. Steven

doi:10.1016/j.ydbio.2017.11.006

Cited by 92 publications

(120 citation statements)

References 30 publications

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“…Transcriptome analysis at the single cell level is a powerful new tool applied effectively to build detailed maps of cellular constituents and their developmental trajectories in various tissues. While multiple studies have generated single-cell transcriptomic data for mouse (Adam et al, 2017;Brunskill et al, 2014;Combes et al, 2019;Magella et al, 2018) and human (Lindstrom et al, 2018;Wang et al, 2018) kidney development, the overwhelming focus in these early phases has been on enumerating the cell types compromising the kidney, with mechanistic exploration delegated for future investigation.…”

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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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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“…2A, red arrows). A heatmap of 67 genes that were previously found to be associated with the different cell types that co-exist within the developing kidney [14,[19][20][21] (Fig. 2B), as well as barplots for selected genes associated with renal-mesenchymal and epithelial cell states ( Fig.…”

Section: Cells At the Early Stage Of Human Kidney Development (Ncam-hmentioning

confidence: 99%

Characterization of splice isoform switching during human kidney development

Wineberg

Kanter

Ben-Haim

et al. 2019

Preprint

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Nephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme -a transient kidney-specific progenitor state -undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron. Faults in this transition can lead to a pediatric malignancy of the kidney called Wilms' tumor that mimics normal kidney development. While kidney development has been characterized at the gene expression level, a comprehensive characterization of alternative splicing is lacking. We therefore performed RNA sequencing on cell populations representing early, intermediate, and late developmental stages of the human fetal kidney, as well as three blastemal-predominant Wilms' tumor patient-derived xenografts. We identified a set of transcripts that are alternatively spliced between the different developmental stages. Moreover, we found that cells from the earliest developmental stage have a mesenchymal splice-isoform profile that is similar to that of blastemal-predominant Wilms' tumors. RNA binding motif enrichment analysis suggests that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate mRNA splice isoform switching during human kidney development. These findings illuminate new molecular mechanisms involved in kidney development and pediatric kidney tumors. KEYWORDSKidney development, RNA sequencing, Alternative splicing, Mesenchymal to epithelial transition (MET), Wilms' tumor HIGHLIGHTS During fetal kidney development, kidney progenitor cells undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron.  RNA sequencing identifies a set of transcripts that undergo splice isoform switching during the mesenchymal to epithelial transition (MET) that occurs in the course of human fetal kidney development.  Cells in the early stages of kidney development have a mesenchymal spliceisoform profile that is similar to that observed in blastemal-predominant Wilms' tumor patient-derived xenografts (WT-PDX) that represent an aggressive subtype of Wilms' tumors.  RNA binding motif enrichment analysis indicates that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate splice isoform switching during human kidney development.

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“…Magella et al [78] also performed scRNA-seq of developing mouse kidney and unexpectedly identified the expression of Gdnf, a key driver of branching morphogenesis of the collecting duct system, in nephrogenic zone stromal cells. GDNF was previously thought to be solely from the cap mesenchyme nephron progenitors.…”

Section: Current Studies In the Field Of Kidney Research That Used Scmentioning

confidence: 99%

“…The kidneys of E14.5 and newborn mouse embryos were analyzed by scRNA-seq [77,78], and 9 and 16 distinct cell types, respectively, were identified in those studies. However, the cell types and lineages at other developing stages are still lacking and deserve to be further explored to obtain more detailed views of molecular and cell lineage transitions during kidney development.…”

Section: Perspectivesmentioning

confidence: 99%

Understanding the Biology and Pathogenesis of the Kidney by Single-Cell Transcriptomic Analysis

Song

Zhang

et al. 2018

Kidney Dis

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Background: Single-cell RNA-seq (scRNA-seq) has recently emerged as a revolutionary and powerful tool for biomedical research. However, there have been relatively few studies using scRNA-seq in the field of kidney study. Summary: scRNA-seq achieves gene expression profiling at single-cell resolution in contrast with the conventional methods of gene expression profiling, which are based on cell population and give averaged values of gene expression of the cells. Single-cell transcriptomic analysis is crucial because individual cells of the same type are highly heterogeneous in gene expression, which reflects the existence of subpopulations, different cellular states, or molecular dynamics, of the cells, and should be resolved for further insights. In addition, gene expression analysis of tissues or organs that usually comprise multiple cell types or subtypes results in data that are not fully applicable to any given cell type. scRNA-seq is capable of identifying all cell types and subtypes in a tissue, including those that are new or present in small quantity. With these unique capabilities, scRNA-seq has been used to dissect molecular processes in cell differentiation and to trace cell lineages in development. It is also used to analyze the cells in a lesion of disease to identify the cell types and molecular dynamics implicated in the injury. With continuous technical improvement, scRNA-seq has become extremely high throughput and cost effective, making it accessible to all laboratories. In the present review article, we provide an overall review of scRNA-seq concerning its history, improvements, and applications. In addition, we describe the available studies in which scRNA-seq was employed in the field of kidney research. Lastly, we discuss other potential uses of scRNA-seq for kidney research. Key Message: This review article provides general information on scRNA-seq and its various uses. Particularly, we summarize the studies in the field of kidney diseases in which scRNA-seq was used and discuss potential additional uses of scRNA-seq for kidney research.

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Cross-platform single cell analysis of kidney development shows stromal cells express Gdnf

Cited by 92 publications

References 30 publications

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

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

Characterization of splice isoform switching during human kidney development

Understanding the Biology and Pathogenesis of the Kidney by Single-Cell Transcriptomic Analysis

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