Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron

Cheng, Hui-Teng; Kim, Mijin; Valerius, M. Todd; Surendran, Kameswaran; Schuster-Gossler, Karin; Gossler, Achim; McMahon, Andrew P.; Kopan, Raphael

doi:10.1242/dev.02887

Cited by 93 publications

(170 citation statements)

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“…Indeed, the inappropriate activity of developmental pathways can be causative of renal disease. Niranjan et al [13] report that over-activity of the Notch pathway in podocytes can lead to apoptosis and resultant proteinuria, while genetic or biochemical suppression of this pathway, which is known to be critical for normal proximal tubular development [14,15], prevents glomerulosclerosis and proteinuria.…”

Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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“…Studies of several signaling pathways, as well as transcription factors, have revealed genes involved in the patterning the nephron including Fgf8 (Grieshammer et al, 2005), Pou3f3 (Nakai et al, 2003),Sprouty (Basson et al, 2005;Basson et al, 2006), Notch/presenillins (Cheng et al, 2007;Cheng et al, 2003;McCright et al, 2002), and Lhx1 (Kobayashi et al, 2005). In particular, genetic studies have shown several members of the Wnt family of lipidmodified secreted glycoproteins have important roles in the initiation and maintenance of nephron formation and branching morphogenesis Kispert et al, 1998;Majumdar et al, 2003;Stark et al, 1994).…”

Section: Screen For Genes In Nephron Formationmentioning

confidence: 99%

Transcriptional profiling of Wnt4 mutant mouse kidneys identifies genes expressed during nephron formation

Valerius

McMahon

2008

Gene Expression Patterns

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The mature nephron forms from a simple epithelial vesicle into an elaborate structure with distinct regions of specialized physiological function. The molecular components driving the process of nephron development are not well understood. To identify genes that may be informative in this process we conducted a transcriptional profiling screen using Wnt4 mutant kidneys. In Wnt4 −/− homozygous mice, condensates and pretubular aggregates are induced, however, epithelial renal vesicles fail to form and subsequent tubulogenesis is blocked. A transcriptional profile comparison between wildtype and Wnt4−/− mutant kidneys at E14.5 was performed using Affymetrix oligonucleotide microarrays to identify nephron-expressed genes. This approach identified 236 genes with expression levels >1.8 fold higher in wildtype versus mutant kidneys, amongst these were a number of known nephron component markers confirming the validity of the screen. These results were further detailed by wholemount in situ hybridization (WISH) of E15.5 urogenital systems (UGS). We annotated the spatial expression pattern of these genes into eight categories of expression. Genes expressed in renal vesicle and their derivatives, structures absent in the mutant, accounted for the largest number of the observed expression patterns. A number of additional genes in areas not directly overlapping the Wnt4 expression domain were also identified including the cap mesenchyme, the collecting duct, and the cortical interstitium. This study provides a useful compendium of molecular markers for the study of nephrogenesis.

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“…In contrast, Notch2, but not Notch1, is essential for marginal zone B-cell development in the spleen 16 . Chen et al 17 reported that only Notch2, but not Notch1, is required for the differentiation of proximal nephron structures. In mature kidney, Murea et al 18 demonstrated that only reactivated Notch1 had a correlation with glomerulosclerosis in human glomerular diseases, while both Notch1 and Notch2 were reactivated.…”

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confidence: 99%