The Experts below are selected from a list of 95166 Experts worldwide ranked by ideXlab platform
Jordan A. Kreidberg - One of the best experts on this subject based on the ideXlab platform.
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dicer function is required in the metanephric mesenchyme for early Kidney Development
American Journal of Physiology-renal Physiology, 2014Co-Authors: Jessica Chu, Jordan A. Kreidberg, Sunder Simslucas, Daniel Bushnell, Andrew J BodnarAbstract:MicroRNAs (miRNAs) are small, noncoding regulatory RNAs that act as posttranscriptional repressors by binding to the 3′-untranslated region (3′-UTR) of target genes. They require processing by Dicer, an RNase III enzyme, to become mature regulatory RNAs. Previous work from our laboratory revealed critical roles for miRNAs in nephron progenitors at midgestation (Ho J, Pandey P, Schatton T, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. J Am Soc Nephrol 22: 1053–1063, 2011). To interrogate roles for miRNAs in the early metanephric mesenchyme, which gives rise to nephron progenitors as well as the renal stroma during Kidney Development, we conditionally ablated Dicer function in this lineage. Despite normal ureteric bud outgrowth and condensation of the metanephric mesenchyme to form nephron progenitors, early loss of miRNAs in the metanephric mesenchyme resulted in severe renal dysgenesis. Nephron progenitors are initially correctly specified in the mutant Kidneys, with normal expression of several transcription factors known to be critical in progenitors, including Six2, Pax2, Sall1, and Wt1. However, there is premature loss of the nephron progenitor marker Cited1, marked apoptosis, and increased expression of the proapoptotic protein Bim shortly after the initial inductive events in early Kidney Development. Subsequently, there is a failure in ureteric bud branching and nephron progenitor differentiation. Taken together, our data demonstrate a previously undetermined requirement for miRNAs during early Kidney organogenesis and indicate a crucial role for miRNAs in regulating the survival of this lineage.
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Angioblast-mesenchyme induction of early Kidney Development is mediated by Wt1 and Vegfa.
Development, 2005Co-Authors: Xiaobo Gao, Melissa H Little, Bree Rumballe, Xing Chen, Mary Taglienti, Jordan A. KreidbergAbstract:Most studies on Kidney Development have considered the interaction of the metanephric mesenchyme and the ureteric bud to be the major inductive event that maintains tubular differentiation and branching morphogenesis. The mesenchyme produces Gdnf, which stimulates branching, and the ureteric bud stimulates continued growth of the mesenchyme and differentiation of nephrons from the induced mesenchyme. Null mutation of the Wt1 gene eliminates outgrowth of the ureteric bud, but Gdnf has been identified as a target of Pax2, but not of Wt1. Using a novel system for microinjecting and electroporating plasmid expression constructs into murine organ cultures, it has been demonstrated that Vegfa expression in the mesenchyme is regulated by Wt1. Previous studies had identified a population of Flk1-expressing cells in the periphery of the induced mesenchyme, and adjacent to the stalk of the ureteric bud, and that Vegfa was able to stimulate growth of Kidneys in organ culture. Here it is demonstrated that signaling through Flk1 is required to maintain expression of Pax2 in the mesenchyme of the early Kidney, and for Pax2 to stimulate expression of Gdnf. However, once Gdnf stimulates branching of the ureteric bud, the Flk1-dependent angioblast signal is no longer required to maintain branching morphogenesis and induction of nephrons. Thus, this work demonstrates the presence of a second set of inductive events, involving the mesenchymal and angioblast populations, whereby Wt1-stimulated expression of Vegfa elicits an as-yet-unidentified signal from the angioblasts, which is required to stimulate the expression of Pax2 and Gdnf, which in turn elicits an inductive signal from the ureteric bud.
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involvement of laminin binding integrins and laminin 5 in branching morphogenesis of the ureteric bud during Kidney Development
Developmental Biology, 2001Co-Authors: Roy Zent, Jordan A. Kreidberg, Kevin T Bush, Robert O Stuart, Martin Pohl, Vito Quaranta, Naohiko Koshikawa, Zemin Wang, Hiroyuki Sakurai, Sanjay K NigamAbstract:Branching morphogenesis of the ureteric bud (UB) [induced by the metanephric mesenchyme (MM)] is necessary for normal Kidney Development. The role of integrins in this complex Developmental process is not well understood. However, the recent advent of in vitro model systems to study branching of UB cells and isolated UB tissue makes possible a more detailed analysis of the integrins involved. We detected integrin subunits alpha3, alpha6, beta1, and beta4 in both the UB and cells derived from the early UB. Blocking the function of each of these integrin subunits individually markedly inhibited branching morphogenesis in cell culture models. However, inhibiting individual integrin function with blocking antibodies in whole Kidney and isolated UB culture only partially inhibited UB branching morphogenesis, suggesting that, in these more complex in vitro systems, multiple integrins are involved in the branching program. In whole organ and isolated bud culture, marked retardation of UB branching was observed only when both alpha3 and alpha6 integrin subunits were inhibited. The alpha6 integrin subunit can be expressed as both alpha6beta1 and alpha6beta4, and both of these beta subunits are important for UB branching morphogenesis in both cell and organ culture. Furthermore, laminin-5, a common ligand for integrins alpha3beta1 and alpha6beta4, was detected in the developing UB and shown to be required for normal UB branching morphogenesis in whole embryonic Kidney organ culture as well as isolated UB culture. Together, these data from UB cell culture, organ culture, and isolated UB culture models indicate that both integrin alpha3 and alpha6 subunits play a direct role in UB branching morphogenesis, as opposed to being modulators of the inductive effects of mesenchyme on UB Development. Furthermore the data are consistent with a role for laminin-5, acting through its alpha3beta1 and/or alpha6beta4 integrin receptors, in UB branching during nephrogenesis. These data may help to partially explain the renal phenotype seen in integrin alpha3 and alpha3/alpha6 subunit-deficient animals.
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wt 1 is required for early Kidney Development
Cell, 1993Co-Authors: Jordan A. Kreidberg, Jerry Pelletier, Hannu Sariola, Janet M Loring, Masahiro Maeda, David E Housman, Rudolf JaenischAbstract:In humans, germline mutations of the WT-1 tumor suppressor gene are associated with both Wilms' tumors and urogenital malformations. To develop a model system for the molecular analysis of urogenital Development, we introduced a mutation into the murine WT-1 tumor suppressor gene by gene targeting in embryonic stem cells. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos revealed a failure of Kidney and gonad Development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the Wolffian duct, and the inductive events that lead to formation of the metanephric Kidney did not occur. In addition, the mutation caused abnormal Development of the mesothelium, heart, and lungs. Our results establish a crucial role for WT-1 in early urogenital Development.
Sanjay K Nigam - One of the best experts on this subject based on the ideXlab platform.
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gene targeted deletion in mice of the ets 1 transcription factor a candidate gene in the jacobsen syndrome Kidney critical region causes abnormal Kidney Development
American Journal of Medical Genetics Part A, 2019Co-Authors: Dongrui Chen, Teresa Mattina, Orsetta Zufardi, Elena Rossi, Kevin T Bush, Sanjay K Nigam, Paul GrossfeldAbstract:Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural Kidney defects occur at an increased frequency in Jacobsen syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.1 Mb "critical region" for Kidney defects in Jacobsen syndrome, which spans ~50 genes. We demonstrate that gene-targeted deletion of Ets-1 in mice results in some of the most common congenital Kidney defects occurring in Jacobsen syndrome, including: duplicated Kidney, hypoplastic Kidney, and dilated renal pelvis and calyces. Taken together, our results implicate Ets-1 in normal mammalian Kidney Development and, potentially, in the pathogenesis of some of the most common types of human structural Kidney defects.
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rho kinase acts at separate steps in ureteric bud and metanephric mesenchyme morphogenesis during Kidney Development
Differentiation, 2006Co-Authors: Tobias N Meyer, Kevin T Bush, Catherine Schwesinger, Rosemary V Sampogna, Duke A Vaughn, Robert O Stuart, Dylan L Steer, Sanjay K NigamAbstract:In this study, five different in vitro assays, which together recapitulate much of Kidney Development, were used to examine the role of the Rho-associated protein serine/threonine kinase (ROCK) in events central to ureteric bud (UB) and metanephric mesenchyme (MM) morphogenensis, in isolation and together. ROCK activity was found to be critical for (1) cell proliferation, growth, and Development of the whole embryonic Kidney in organ culture, (2) tip and stalk formation in cultures of isolated UBs, and (3) migration of MM cells (in a novel MM migration assay) during their condensation at UB tips (in a UB/MM recombination assay). Together, the data indicate selective involvement of Rho/ROCK in distinct morphogenetic processes necessary for Kidney Development and that the coordination of these events by Rho/ROCK provides a potential mechanism to regulate overall branching patterns, nephron formation, and thus, Kidney architecture.
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organic anion and cation transporter expression and function during embryonic Kidney Development and in organ culture models
Kidney International, 2006Co-Authors: Kevin T Bush, Duke A Vaughn, Douglas H Sweet, Satish A Eraly, Sanjay K NigamAbstract:Organic anion and cation transporters (OATs, OCTs, and OCTNs) mediate the proximal tubular secretion of numerous clinically important compounds, including various commonly prescribed pharmaceuticals. Here, we report determination of the ontogeny of these transporters and of NaPi2 and SGLT1, using quantitative polymerase chain reaction (QPCR) to determine expression levels of transporter genes in rat embryonic Kidneys on each day of gestation from embryonic day (ed) 13 to ed18, in cultures of induced and uninduced metanephric mesenchyme (MM), and on each day of 1 week of whole embryonic Kidney (WEK) culture. We also examined ontogeny of Oat1 protein expression in rat embryonic Kidney by immunohistochemistry. Finally, we used uptake of fluorescein (FL) as a novel in vitro functional assay of OAT expression in WEK and MM. Developmental induction of OAT and OCT genes does not occur uniformly: some genes are induced early (e.g., Oat1 and Oat3, potential early markers of proximal tubulogenesis), and others after Kidney Development is relatively advanced (e.g., Oct1, a potential marker of terminal differentiation). The ontogeny of transporter genes in WEK and MM is similar to that observed in vivo, indicating that these organ culture systems may represent convenient in vitro models to study the Developmental induction of OATs, OCTs, and OCTNs. Functional transport was evidenced by accumulation of FL in the developing tubule in WEK and MM organ cultures. Our findings on the renal ontogeny of OATs and OCTs could carry implications both for the Development of more rational therapeutics for premature infants, as well as for our understanding of proximal tubule differentiation.
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changes in gene expression patterns in the ureteric bud and metanephric mesenchyme in models of Kidney Development
Kidney International, 2003Co-Authors: Robert O Stuart, Kevin T Bush, Sanjay K NigamAbstract:Changes in gene expression patterns in the ureteric bud and metanephric mesenchyme in models of Kidney Development. Background In a recent study, the pattern of gene expression during Development of the rat Kidney was analyzed using high-density DNA array technology (Stuart RO, Bush KT, Nigam SK, Proc Natl Acad Sci USA 98:5649–5654, 2001). This approach, while shedding light on global patterns of gene expression in the developing Kidney, does not provide insight into the contributions of genes that might be part of the morphogenetic program of the ureteric bud (UB) and metanephric mesenchyme (MM), the two tissues that interact closely during nephron formation. Methods We have now used high-density DNA arrays together with a double in vitro transcription (dIVT) approach to examine gene expression patterns in in vitro models for morphogenesis of the rat UB (isolated UB culture) and MM (coculture with embryonic spinal cord) and compared this data with patterns of gene expression in the whole embryonic Kidney at different stages of Development. Results The results indicate that different sets of genes are expressed in the UB and MM as morphogenesis occurs. The dIVT data from the in vitro UB and MM culture models was clustered hierarchically with single IVT data from the whole embryonic Kidney obtained at different stages of Development, and the global patterns of gene expression were remarkably compatible, supporting the validity of the approach. The potential roles of genes whose expression was associated with the individual tissues were examined, and several pathways were identified that could have roles in Kidney Development. For example, hepatocyte nuclear factor-6 (HNF-6), a transcription factor potentially upstream in a pathway leading to the expression of KSP-cadherin was highly expressed in the UB. Embigin, a cell adhesion molecule important in cell/extracellular matrix (ECM) interactions, was also found in the UB and may serve as a Dolichos biflorus binding protein in the Kidney. ADAM10, a disintegrin-metalloprotease involved in Delta-Notch signaling and perhaps Slit–Robo signaling, was also highly expressed in late UB. Celsr-3, a protein, which along with members of the Wnt-frizzled transduction cascade, might be involved in the polarization of the forming nephron, was found to be highly expressed in differentiating MM. DDR2, a member of the discoidin domain receptor family, which is thought to function in the activation of matrix metalloproteinase-2 (MMP-2), was also found to be highly expressed in differentiating MM. It is also interesting to note that almost 10% of the highly expressed genes in both tissues were associated with neuronal growth and/or differentiation. Conclusion The data presented in this study point to the power of combining in vitro models of Kidney Development with high-density DNA arrays to identify the genes involved in the morphogenetic process. Clear differences were found between patterns of genes expressed by the UB and MM at different stages of morphogenesis, and many of these were associated with neuronal growth and/or differentiation. Together, the high-density microarray data not only begin to suggest how separate genetic programs in the UB and MM orchestrate the formation of the whole Kidney, but also suggest the involvement of heretofore largely unexplored Developmental pathways (involving HNF-6 , ADAM-10 , Celsr-3 , DDR2 , and other genes) in nephrogenesis.
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involvement of laminin binding integrins and laminin 5 in branching morphogenesis of the ureteric bud during Kidney Development
Developmental Biology, 2001Co-Authors: Roy Zent, Jordan A. Kreidberg, Kevin T Bush, Robert O Stuart, Martin Pohl, Vito Quaranta, Naohiko Koshikawa, Zemin Wang, Hiroyuki Sakurai, Sanjay K NigamAbstract:Branching morphogenesis of the ureteric bud (UB) [induced by the metanephric mesenchyme (MM)] is necessary for normal Kidney Development. The role of integrins in this complex Developmental process is not well understood. However, the recent advent of in vitro model systems to study branching of UB cells and isolated UB tissue makes possible a more detailed analysis of the integrins involved. We detected integrin subunits alpha3, alpha6, beta1, and beta4 in both the UB and cells derived from the early UB. Blocking the function of each of these integrin subunits individually markedly inhibited branching morphogenesis in cell culture models. However, inhibiting individual integrin function with blocking antibodies in whole Kidney and isolated UB culture only partially inhibited UB branching morphogenesis, suggesting that, in these more complex in vitro systems, multiple integrins are involved in the branching program. In whole organ and isolated bud culture, marked retardation of UB branching was observed only when both alpha3 and alpha6 integrin subunits were inhibited. The alpha6 integrin subunit can be expressed as both alpha6beta1 and alpha6beta4, and both of these beta subunits are important for UB branching morphogenesis in both cell and organ culture. Furthermore, laminin-5, a common ligand for integrins alpha3beta1 and alpha6beta4, was detected in the developing UB and shown to be required for normal UB branching morphogenesis in whole embryonic Kidney organ culture as well as isolated UB culture. Together, these data from UB cell culture, organ culture, and isolated UB culture models indicate that both integrin alpha3 and alpha6 subunits play a direct role in UB branching morphogenesis, as opposed to being modulators of the inductive effects of mesenchyme on UB Development. Furthermore the data are consistent with a role for laminin-5, acting through its alpha3beta1 and/or alpha6beta4 integrin receptors, in UB branching during nephrogenesis. These data may help to partially explain the renal phenotype seen in integrin alpha3 and alpha3/alpha6 subunit-deficient animals.
Melissa H Little - One of the best experts on this subject based on the ideXlab platform.
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mammalian Kidney Development principles progress and projections
Cold Spring Harbor Perspectives in Biology, 2012Co-Authors: Melissa H Little, Andrew P McmahonAbstract:The mammalian Kidney is a vital organ with considerable cellular complexity and functional diversity. Kidney Development is notable for requiring distinct but coincident tubulogenic processes involving reciprocal inductive signals between mesenchymal and epithelial progenitor compartments. Key molecular pathways mediating these interactions have been identified. Further, advances in the analysis of gene expression and gene activity, coupled with a detailed knowledge of cell origins, are enhancing our understanding of Kidney morphogenesis and unraveling the normal processes of postnatal repair and identifying disease-causing mechanisms. This article focuses on recent insights into central regulatory processes governing organ assembly and renal disease, and predicts future directions for the field.
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identification of anchor genes during Kidney Development defines ontological relationships molecular subcompartments and regulatory pathways
PLOS ONE, 2011Co-Authors: Rathi D Thiagarajan, Bree Rumballe, Kylie Georgas, Emmanuelle Lesieur, Han Sheng Chiu, Darrin Taylor, Dave Tang, Sean M Grimmond, Melissa H LittleAbstract:The Development of the mammalian Kidney is well conserved from mouse to man. Despite considerable temporal and spatial data on gene expression in mammalian Kidney Development, primarily in rodent species, there is a paucity of genes whose expression is absolutely specific to a given anatomical compartment and/or Developmental stage, defined here as ‘anchor’ genes. We previously generated an atlas of gene expression in the developing mouse Kidney using microarray analysis of anatomical compartments collected via laser capture microdissection. Here, this data is further analysed to identify anchor genes via stringent bioinformatic filtering followed by high resolution section in situ hybridisation performed on 200 transcripts selected as specific to one of 11 anatomical compartments within the midgestation mouse Kidney. A total of 37 anchor genes were identified across 6 compartments with the early proximal tubule being the compartment richest in anchor genes. Analysis of minimal and evolutionarily conserved promoter regions of this set of 25 anchor genes identified enrichment of transcription factor binding sites for Hnf4a and Hnf1b, RbpJ (Notch signalling), PPARγ:RxRA and COUP-TF family transcription factors. This was reinforced by GO analyses which also identified these anchor genes as targets in processes including epithelial proliferation and proximal tubular function. As well as defining anchor genes, this large scale validation of gene expression identified a further 92 compartment-enriched genes able to subcompartmentalise key processes during murine renal organogenesis spatially or ontologically. This included a cohort of 13 ureteric epithelial genes revealing previously unappreciated compartmentalisation of the collecting duct system and a series of early tubule genes suggesting that segmentation into proximal tubule, loop of Henle and distal tubule does not occur until the onset of glomerular vascularisation. Overall, this study serves to illuminate previously ill-defined stages of patterning and will enable further refinement of the lineage relationships within mammalian Kidney Development.
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definition and spatial annotation of the dynamic secretome during early Kidney Development
Developmental Dynamics, 2006Co-Authors: Gemma Martinez, Bree Rumballe, Kylie Georgas, Darrin Taylor, Sean M Grimmond, Grant A Challen, Melissa J Davis, Rohan D Teasdale, Melissa H LittleAbstract:The term "secretome" has been defined as a set of secreted proteins (Grimmond et al. [2003] Genome Res 13:1350-1359). The term "secreted protein" encompasses all proteins exported from the cell including growth factors, extracellular proteinases, morphogens, and extracellular matrix molecules. Defining the genes encoding secreted proteins that change in expression during organogenesis, the dynamic secretome, is likely to point to key drivers of morphogenesis. Such secreted proteins are involved in the reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM) that occur during organogenesis of the metanephros. Some key metanephric secreted proteins have been identified, but many remain to be determined. In this study, microarray expression profiling of E10.5, E11.5, and E13.5 Kidney and consensus bioinformatic analysis were used to define a dynamic secretome of early metanephric Development. In situ hybridisation was used to confirm microarray results and clarify spatial expression patterns for these genes. Forty-one secreted factors were dynamically expressed between the E10.5 and E13.5 timeframe profiled, and 25 of these factors had not previously been implicated in Kidney Development. A text-based anatomical ontology was used to spatially annotate the expression pattern of these genes in cultured metanephric explants.
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pax2 activates wnt4 expression during mammalian Kidney Development
Journal of Biological Chemistry, 2006Co-Authors: Elena Torban, Alison Dziarmaga, Diana M Iglesias, Tatiana Vassilieva, Maria Teresa Discenza, Melissa H Little, Michael R. Eccles, Jerry Pelletier, Paul GoodyerAbstract:The transcription factor PAX2 is expressed during normal Kidney Development and is thought to influence outgrowth and branching of the ureteric bud. Mice with homozygous null Pax2 mutations have Developmental defects of the midbrain-hindbrain region, optic nerve, and ear and are anephric. During nephrogenesis, PAX2 is also expressed by mesenchymal cells as they cluster and reorganize to form proximal elements of each nephron, but the function of PAX2 in these cells is unknown. In this study we hypothesized that PAX2 activates expression of WNT4, a secreted glycoprotein known to be critical for successful nephrogenesis. PAX2 protein was identified in distal portions of the S-shaped body, and the protein persists in the emerging proximal tubules of murine fetal Kidney. PAX2 activated WNT4 promoter activity 5-fold in co-transfection assays with JTC12 cells derived from the proximal tubule. Inspection of the 5'-flanking sequence of the human WNT4 gene identified three novel PAX2 recognition motifs; each exhibited specific PAX2 protein binding in electromobility shift assays. Two motifs were contained within a completely duplicated 0.66-kb cassette. Transfection of JTC12 cells with a PAX2 expression vector was associated with a 7-fold increase in endogenous WNT4 mRNA. In contrast, Wnt4 mRNA was decreased by 60% in mesenchymal cell condensates of fetal Kidney from mice with a heterozygous Pax2 mutation. We speculated that a key function of PAX2 is to activate WNT4 gene expression in metanephric mesenchymal cells as they differentiate to form elements of the renal tubules.
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Angioblast-mesenchyme induction of early Kidney Development is mediated by Wt1 and Vegfa.
Development, 2005Co-Authors: Xiaobo Gao, Melissa H Little, Bree Rumballe, Xing Chen, Mary Taglienti, Jordan A. KreidbergAbstract:Most studies on Kidney Development have considered the interaction of the metanephric mesenchyme and the ureteric bud to be the major inductive event that maintains tubular differentiation and branching morphogenesis. The mesenchyme produces Gdnf, which stimulates branching, and the ureteric bud stimulates continued growth of the mesenchyme and differentiation of nephrons from the induced mesenchyme. Null mutation of the Wt1 gene eliminates outgrowth of the ureteric bud, but Gdnf has been identified as a target of Pax2, but not of Wt1. Using a novel system for microinjecting and electroporating plasmid expression constructs into murine organ cultures, it has been demonstrated that Vegfa expression in the mesenchyme is regulated by Wt1. Previous studies had identified a population of Flk1-expressing cells in the periphery of the induced mesenchyme, and adjacent to the stalk of the ureteric bud, and that Vegfa was able to stimulate growth of Kidneys in organ culture. Here it is demonstrated that signaling through Flk1 is required to maintain expression of Pax2 in the mesenchyme of the early Kidney, and for Pax2 to stimulate expression of Gdnf. However, once Gdnf stimulates branching of the ureteric bud, the Flk1-dependent angioblast signal is no longer required to maintain branching morphogenesis and induction of nephrons. Thus, this work demonstrates the presence of a second set of inductive events, involving the mesenchymal and angioblast populations, whereby Wt1-stimulated expression of Vegfa elicits an as-yet-unidentified signal from the angioblasts, which is required to stimulate the expression of Pax2 and Gdnf, which in turn elicits an inductive signal from the ureteric bud.
Iain A. Drummond - One of the best experts on this subject based on the ideXlab platform.
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zebrafish slc4a2 ae2 anion exchanger cdna cloning mapping functional characterization and localization
American Journal of Physiology-renal Physiology, 2005Co-Authors: Boris E Shmukler, Christine E Kurschat, Gabriele E Ackermann, Lianwei Jiang, Yi Zhou, Bruce A Barut, Alan K Stuarttilley, Jinhua Zhao, Leonard I Zon, Iain A. DrummondAbstract:Although the zebrafish has been used increasingly for the study of pronephric Kidney Development, studies of renal ion transporters and channels of the zebrafish remain few. We report the cDNA clon...
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Kidney Development and disease in the zebrafish
Journal of The American Society of Nephrology, 2005Co-Authors: Iain A. DrummondAbstract:Unraveling the molecular pathogenesis of human disease presents many experimental challenges, not the least of which is that experiments on humans are generally frowned upon. Model organisms, including the zebrafish, allow for experimental analysis of gene function and the detailed characterization of disease processes. Zebrafish have matured as a vertebrate model organism now that genetic tools for targeted “knockdowns” and unbiased mutagenesis approaches are in hand. The fish larval pronephros is a relevant Kidney in which to pursue many aspects of human Kidney Development and disease. This short review outlines recent progress in applying the zebrafish pronephros to issues of human health and Development.
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The zebrafish pronephros: a genetic system for studies of Kidney Development
Pediatric Nephrology, 2000Co-Authors: Iain A. DrummondAbstract:The zebrafish, as a model system for vertebrate Development, offers distinct experimental advantages for studies of organogenesis. The simplicity of the zebrafish pronephros, the feasibility of isolating large numbers of mutants, and the growth in infrastructure for genomics makes the zebrafish an attractive system for the analysis of Kidney Development. Mutants affecting several aspects of nephrogenesis, including differentiation of the intermediate mesoderm, nephron patterning, epithelial polarity, and angiogenesis, have been isolated. Analysis of mutant phenotypes and the cloning of mutant genes has revealed: (1) a role for bone morphogenetic proteins in patterning the ventral mesoderm, (2) an essential role for the pax2.1 gene in pronephric Development, (3) multiple loci required for establishing epithelial polarity in the pronephric duct, (4) a central role for podocytes in directing glomerulogenesis, and (5) 15 loci associated with cystic malDevelopment in the pronephros. The striking similarities of pronephric cell types to those found in higher vertebrates, as well as the conservation of Kidney-specific gene expression patterns, suggest that insights gained from studies in zebrafish will be broadly applicable to cell differentiation in the Kidney.
Andrew P Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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mammalian Kidney Development principles progress and projections
Cold Spring Harbor Perspectives in Biology, 2012Co-Authors: Melissa H Little, Andrew P McmahonAbstract:The mammalian Kidney is a vital organ with considerable cellular complexity and functional diversity. Kidney Development is notable for requiring distinct but coincident tubulogenic processes involving reciprocal inductive signals between mesenchymal and epithelial progenitor compartments. Key molecular pathways mediating these interactions have been identified. Further, advances in the analysis of gene expression and gene activity, coupled with a detailed knowledge of cell origins, are enhancing our understanding of Kidney morphogenesis and unraveling the normal processes of postnatal repair and identifying disease-causing mechanisms. This article focuses on recent insights into central regulatory processes governing organ assembly and renal disease, and predicts future directions for the field.
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six2 defines and regulates a multipotent self renewing nephron progenitor population throughout mammalian Kidney Development
Cell Stem Cell, 2008Co-Authors: Akio Kobayashi, Guillermo Oliver, Todd M Valerius, Joshua W Mugford, Thomas J Carroll, Michelle Self, Andrew P McmahonAbstract:Nephrons, the basic functional units of the Kidney, are generated repetitively during Kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted Developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of Kidney Development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
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Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during Kidney Development
Development (Cambridge England), 2005Co-Authors: Kin Ming Kwan, Andrew P Mcmahon, Thomas J Carroll, Cathy MendelsohnAbstract:Kidney organogenesis requires the morphogenesis of epithelial tubules. Inductive interactions between the branching ureteric buds and the metanephric mesenchyme lead to mesenchyme-to-epithelium transitions and tubular morphogenesis to form nephrons, the functional units of the Kidney. The LIM-class homeobox gene Lim1 is expressed in the intermediate mesoderm, nephric duct, mesonephric tubules, ureteric bud, pretubular aggregates and their derivatives. Lim1-null mice lack Kidneys because of a failure of nephric duct formation, precluding studies of the role of Lim1 at later stages of Kidney Development. Here, we show that Lim1 functions in distinct tissue compartments of the developing metanephros for both proper Development of the ureteric buds and the patterning of renal vesicles for nephron formation. These observations suggest that Lim1 has essential roles in multiple steps of epithelial tubular morphogenesis during Kidney organogenesis. We also demonstrate that the nephric duct is essential for the elongation and maintenance of the adjacent Mullerian duct, the anlage of the female reproductive tract.
