A Secreted BMP Antagonist, Cer1, Fine Tunes the Spatial Organization of the Ureteric Bud Tree during Mouse Kidney Development

Pappa2 is a metalloproteinase which specifically cleaves IGFBP-3 and IGFBP-5 and in turn releases IGF-1. Recently, we have shown that a subcongenic Dahl salt-sensitive (SS) rat strain containing a 0.71 Mbp of chromosome 13 which includes Pappa2 gene from salt-insensitive Brown Norway (26-P strain) is protected significantly (24 mmHg) from salt-induced hypertension (Cowley et al., 2016). Although it is recognized that Pappa2 modulates development of bone size, cranial cartilage and angiogenesis, its role in kidney development and function is unknown. The present study determined the contribution of Pappa2 to nephron development by comparing SS and 26-P rat strains. It was found that Pappa2 mRNA expression was 5-fold higher in embryonic kidney (day 20.5) of the salt-resistant 26-P rats compared with age-matched SS rats. Pappa2 mRNA expression significantly increased with age of kidney reaching a maximum at postnatal day 5 in both strains. Pappa2 mRNA expression at postnatal day 15 was found to be 9-fold higher in the kidney of 26-P compared with SS strain. Immunohistochemistry studies revealed that Pappa2 co-localized with IGFBP-5 in the ureteric bud indicating that Pappa2 could be important for ureteric branching and nephron endowment. Glomerulus/mm 2 was therefore determined by counting total number of glomeruli in kidney sections from pups starting from P0 to P20. The salt-resistant 26-P congenic strain exhibited significantly greater nephron density 9.03 and 7.07 glo/mm 2 compared to 6.89 and 4.85 glo/mm 2 in SS rat at day P15 and P20, respectively. It appears that the Brown Norway pappa2 allele variant prevents the reduced nephron numbers observed in SS rats and thereby protects these congenic rats from salt-induced hypertension.

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Sulphated proteoglycan is required for collecting duct growth and branching but not nephron formation during kidney development

Development ◽

10.1242/dev.121.5.1507 ◽

1995 ◽

Vol 121 (5) ◽

pp. 1507-1517 ◽

Cited By ~ 8

Author(s):

J. Davies ◽

M. Lyon ◽

J. Gallagher ◽

D. Garrod

Keyword(s):

Kidney Development ◽

Collecting Duct ◽

Sodium Chlorate ◽

Ureteric Bud ◽

Nephron Differentiation ◽

Bud Growth ◽

Nephron Development ◽

Sulphated Glycosaminoglycans ◽

Sulphated Proteoglycan ◽

Hepatocyte Growth

Kidney epithelia have separate origins; collecting ducts develop by ureteric bud growth and arborisation, nephrons by induced mesenchyme-epithelium transition. Both express sulphated glycosaminoglycans (GAGs) which are strikingly upregulated during nephron differentiation. However, sodium chlorate, an inhibitor of GAG sulphation, and the GAG-degrading enzymes heparitinase plus chondroitinase, did not prevent nephron development. In contrast, ureteric bud growth and branching were reversibly inhibited by the above reagents, the inhibition correlating quantitatively with sulphated GAG deprivation caused by a range of chlorate concentrations. Growth and branching could be independently restored during GAG deprivation by hepatocyte growth factor and phorbol-12-myristate acetate (PMA) respectively. Together these signalling effectors stimulated both branch initiation and growth. Thus growth and morphogenesis of ureteric bud involve distinct signalling pathways both regulated by GAGs.

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Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: implications for terminal nephron differentiation

AJP Renal Physiology ◽

10.1152/ajprenal.00370.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. F899-F909 ◽

Cited By ~ 26

Author(s):

Zubaida Saifudeen ◽

Susana Dipp ◽

Hao Fan ◽

Samir S. El-Dahr

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Dna Binding ◽

Spatial Organization ◽

Kidney Development ◽

Collecting Duct ◽

Proximal Promoter ◽

Bradykinin B2 Receptor ◽

Nephron Differentiation ◽

Terminal Nephron

Despite a wealth of knowledge regarding the early steps of epithelial differentiation, little is known about the mechanisms responsible for terminal nephron differentiation. The bradykinin B2 receptor (B2R) regulates renal function and integrity, and its expression is induced during terminal nephron differentiation. This study investigates the transcriptional regulation of the B2R during kidney development. The rat B2R 5′-flanking region has a highly conserved cis-acting enhancer in the proximal promoter consisting of contiguous binding sites for the transcription factors cAMP response element binding protein (CREB), p53, and Krüppel-like factor (KLF-4). The B2R enhancer drives reporter gene expression in inner medullary collecting duct-3 cells but is considerably weaker in other cell types. Site-directed mutagenesis and expression of dominant negative mutants demonstrated the requirement of CREB DNA binding and Ser-133 phosphorylation for optimal enhancer function. Moreover, helical phasing experiments showed that disruption of the spatial organization of the enhancer inhibits B2R promoter activity. Several lines of evidence indicate that cooperative interactions among the three transcription factors occur in vivo during terminal nephron differentiation: 1) CREB, p53, and KLF-4 are coexpressed in B2R-positive differentiating cells; 2) the maturational expression of B2R correlates with CREB/p53/KLF-4 DNA-binding activity; 3) assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation; and 4) CREB and p53 occupancy of the B2R enhancer is cooperative. These results demonstrate that combinatorial interactions among the transcription factors, CREB, p53, and KLF-4, and the coactivator CBP, may be critical for the regulation of B2R gene expression during terminal nephron differentiation.

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Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse kidney development

Kidney International ◽

10.1038/ki.2009.95 ◽

2009 ◽

Vol 76 (1) ◽

pp. 54-62 ◽

Cited By ~ 9

Author(s):

Xiaohong Li ◽

Deborah P. Hyink ◽

Brian Radbill ◽

Marius Sudol ◽

Haojiang Zhang ◽

...

Keyword(s):

Protein Kinase ◽

Kidney Development ◽

Mouse Kidney

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Recent genetic studies of mouse kidney development

Current Opinion in Genetics & Development ◽

10.1016/j.gde.2004.07.009 ◽

2004 ◽

Vol 14 (5) ◽

pp. 550-557 ◽

Cited By ~ 78

Author(s):

Jing Yu ◽

Andrew P McMahon ◽

M Todd Valerius

Keyword(s):

Kidney Development ◽

Mouse Kidney ◽

Genetic Studies

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Genetic Dissection of Cadherin Function during Nephrogenesis

Molecular and Cellular Biology ◽

10.1128/mcb.22.5.1474-1487.2002 ◽

2002 ◽

Vol 22 (5) ◽

pp. 1474-1487 ◽

Cited By ~ 58

Author(s):

Ulf Dahl ◽

Anders Sjödin ◽

Lionel Larue ◽

Glenn L. Radice ◽

Stefan Cajander ◽

...

Keyword(s):

Kidney Development ◽

Morphological Changes ◽

Genetic Dissection ◽

Metanephric Mesenchyme ◽

Ureteric Bud ◽

Metanephric Kidney ◽

The Individual ◽

Deficient Mice

ABSTRACT The distinct expression of R-cadherin in the induced aggregating metanephric mesenchyme suggests that it may regulate the mesenchymal-epithelial transition during kidney development. To address whether R-cadherin is required for kidney ontogeny, R-cadherin-deficient mice were generated. These mice appeared to be healthy and were fertile, demonstrating that R-cadherin is not essential for embryogenesis. The only kidney phenotype of adult mutant animals was the appearance of dilated proximal tubules, which was associated with an accumulation of large intracellular vacuoles. Morphological analysis of nephrogenesis in R-cadherin −/− mice in vivo and in vitro revealed defects in the development of both ureteric bud-derived cells and metanephric mesenchyme-derived cells. First, the morphology and organization of the proximal parts of the ureteric bud epithelium were altered. Interestingly, these morphological changes correlated with an increased rate of apoptosis and were further supported by perturbed branching and patterning of the ureteric bud epithelium during in vitro differentiation. Second, during in vitro studies of mesenchymal-epithelial conversion, significantly fewer epithelial structures developed from R-cadherin −/− kidneys than from wild-type kidneys. These data suggest that R-cadherin is functionally involved in the differentiation of both mesenchymal and epithelial components during metanephric kidney development. Finally, to investigate whether the redundant expression of other classic cadherins expressed in the kidney could explain the rather mild kidney defects in R-cadherin-deficient mice, we intercrossed R-cadherin −/− mice with cadherin-6−/− , P-cadherin −/−, and N-cadherin +/− mice. Surprisingly, however, in none of the compound knockout strains was kidney development affected to a greater extent than within the individual cadherin knockout strains.

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Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development

Development ◽

10.1242/dev.128.16.3105 ◽

2001 ◽

Vol 128 (16) ◽

pp. 3105-3115 ◽

Cited By ~ 9

Author(s):

Ryuichi Nishinakamura ◽

Yuko Matsumoto ◽

Kazuki Nakao ◽

Kenji Nakamura ◽

Akira Sato ◽

...

Keyword(s):

Kidney Development ◽

Perinatal Period ◽

Homozygous Deletion ◽

Homeotic Gene ◽

Metanephric Mesenchyme ◽

Ureteric Bud ◽

Mouse Homolog ◽

Tubule Formation ◽

Murine Homolog ◽

Inductive Signal

SALL1 is a mammalian homolog of the Drosophilaregion-specific homeotic gene spalt (sal); heterozygous mutations in SALL1 in humans lead to Townes-Brocks syndrome. We have isolated a mouse homolog of SALL1 (Sall1) and found that mice deficient in Sall1 die in the perinatal period and that kidney agenesis or severe dysgenesis are present. Sall1 is expressed in the metanephric mesenchyme surrounding ureteric bud; homozygous deletion ofSall1 results in an incomplete ureteric bud outgrowth, a failure of tubule formation in the mesenchyme and an apoptosis of the mesenchyme. This phenotype is likely to be primarily caused by the absence of the inductive signal from the ureter, as the Sall1-deficient mesenchyme is competent with respect to epithelial differentiation. Sall1 is therefore essential for ureteric bud invasion, the initial key step for metanephros development.

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β-catenin regulates the formation of multiple nephron segments in the mouse kidney

Scientific Reports ◽

10.1038/s41598-019-52255-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Patrick Deacon ◽

Charles W. Concodora ◽

Eunah Chung ◽

Joo-Seop Park

Keyword(s):

Kidney Development ◽

Critical Role ◽

Mouse Kidney ◽

Proximal Tubules ◽

Stable Form ◽

Loss Of Function ◽

Nephron Segments ◽

Mesenchymal To Epithelial Transition ◽

Nephron Progenitors ◽

Nephron Segmentation

Abstract The nephron is composed of distinct segments that perform unique physiological functions. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron segmentation after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Expression of a stable form of β-catenin in epithelial nephron progenitors blocked the proper formation of all nephron segments, suggesting tight regulation of β-catenin signaling during nephron segmentation. This work shows that β-catenin regulates the formation of multiple nephron segments along the proximo-distal axis of the mammalian nephron.

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Regulation of BMP7 expression during kidney development

Development ◽

10.1242/dev.125.17.3473 ◽

1998 ◽

Vol 125 (17) ◽

pp. 3473-3482 ◽

Cited By ~ 8

Author(s):

R.E. Godin ◽

N.T. Takaesu ◽

E.J. Robertson ◽

A.T. Dudley

Keyword(s):

Wnt Signaling ◽

Kidney Development ◽

Tooth Development ◽

Expression Patterns ◽

Wnt Signaling Pathway ◽

Sodium Chlorate ◽

Bmp Signaling ◽

Proteoglycan Synthesis ◽

Metanephric Mesenchyme ◽

Ureteric Bud

Members of the Bone Morphogenetic Protein (BMP) family exhibit overlapping and dynamic expression patterns throughout embryogenesis. However, little is known about the upstream regulators of these important signaling molecules. There is some evidence that BMP signaling may be autoregulative as demonstrated for BMP4 during tooth development. Analysis of BMP7 expression during kidney development, in conjunction with studies analyzing the effect of recombinant BMP7 on isolated kidney mesenchyme, suggest that a similar mechanism may operate for BMP7. We have generated a beta-gal-expressing reporter allele at the BMP7 locus to closely monitor expression of BMP7 during embryonic kidney development. In contrast to other studies, our analysis of BMP7/lacZ homozygous mutant embryos, shows that BMP7 expression is not subject to autoregulation in any tissue. In addition, we have used this reporter allele to analyze the expression of BMP7 in response to several known survival factors (EGF, bFGF) and inducers of metanephric mesenchyme, including the ureteric bud, spinal cord and LiCl. These studies show that treatment of isolated mesenchyme with EGF or bFGF allows survival of the mesenchyme but neither factor is sufficient to maintain BMP7 expression in this population of cells. Rather, BMP7 expression in the mesenchyme is contingent on an inductive signal. Thus, the reporter allele provides a convenient marker for the induced mesenchyme. Interestingly LiCl has been shown to activate the Wnt signaling pathway, suggesting that BMP7 expression in the mesenchyme is regulated by a Wnt signal. Treatment of whole kidneys with sodium chlorate to disrupt proteoglycan synthesis results in the loss of BMP7 expression in the mesenchyme whereas expression in the epithelial components of the kidney are unaffected. Heterologous recombinations of ureteric bud with either limb or lung mesenchyme demonstrate that expression of BMP7 is maintained in this epithelial structure. Taken together, these data indicate that BMP7 expression in the epithelial components of the kidney is not dependent on cell-cell or cell-ECM interactions with the metanephric mesenchyme. By contrast, BMP7 expression in the metanephric mesenchyme is dependent on proteoglycans and possibly Wnt signaling.

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