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Andrew P Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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genetic manipulation of ureteric bud tip progenitors in the Mammalian Kidney through an adamts18 enhancer driven tet on inducible system
Developmental Biology, 2020Co-Authors: Elisabeth A. Rutledge, Nils O Lindstrom, Odysse Michos, Andrew P McmahonAbstract:Abstract The ureteric epithelial progenitor (UEP) population within the embryonic Kidney generates the arborized epithelial network of the Kidney’s collecting system and plays a critical role in the expansion and induction of the surrounding nephron progenitor pool. Adamts18 shows UEP- restricted expression in the Kidney and progenitor tip-restricted expression in several other organs undergoing branching epithelial growth. Adamts18 is encoded by 23 exons. Genetic removal of genomic sequence spanning exons 1 to 3 led to a specific loss of Adamts18 expression in UEPs, suggesting this region may encode a UEP-specific enhancer. Intron 2 (3 kb) was shown to have enhancer activity driving expression of the doxycycline inducible tet-on transcriptional regulator (rtTA) in an Adamts18en-rtTA transgenic mouse strain. Crossing Adamts18en-rtTA mice to a doxycycline dependent GFP reporter mouse enabled the live imaging of embryonic Kidney explants. This facilitated the analysis of ureteric epithelial branching events at the cellular level. Ablation of UEPs at the initiation of ureteric bud outgrowth through the doxycycline-mediated induction of Diphtheria Toxin A (DTA) generated a range of phenotypes from complete Kidneys agenesis, to duplex Kidneys with double ureters. The latter outcome points to the potential of regulative processes to restore UEPs. In contrast, overexpression of YAP prior to ureteric bud outgrowth led to a complete failure of Kidney development. Elevating YAP levels at later stages retarded branching growth. A similar phenotype was observed with the overexpression of MYC within the branch-tip localized UEP population. These experiments showcase the utility of the Adamts18en-rtTA transgenic model to the investigation of cellular and molecular events specific to branch tip progenitors within the Mammalian Kidney complementing existing CRE-dependent genetic tools. Further, the illustrative examples point to areas where new insight may be gained into the regulation of UEP programs.
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Cellular heterogeneity in the ureteric progenitor niche and distinct profiles of branching morphogenesis in organ development
Development, 2017Co-Authors: Elisabeth A. Rutledge, Jean-denis Benazet, Andrew P McmahonAbstract:Branching morphogenesis creates arborized epithelial networks. In the Mammalian Kidney, an epithelial progenitor pool at ureteric branch tips (UBTs) creates the urine-transporting collecting system. Using region-specific mouse reporter strains, we performed an RNA-seq screen, identifying tip- and stalk-enriched gene sets in the developing collecting duct system. Detailed in situ hybridization studies of tip-enriched predictions identified UBT-enriched gene sets conserved between the mouse and human Kidney. Comparative spatial analysis of their UBT niche expression highlighted distinct patterns of gene expression revealing novel molecular heterogeneity within the UBT progenitor population. To identify Kidney-specific and shared programs of branching morphogenesis, comparative expression studies on the developing mouse lung were combined with in silico analysis of the developing mouse salivary gland. These studies highlight a shared gene set with multi-organ tip enrichment and a gene set specific to UBTs. This comprehensive analysis extends our current understanding of the ureteric branch tip niche.
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development of the Mammalian Kidney
Current Topics in Developmental Biology, 2016Co-Authors: Andrew P McmahonAbstract:The basic unit of Kidney function is the nephron. In the mouse, around 14,000 nephrons form in a 10-day period extending into early neonatal life, while the human fetus forms the adult complement of nephrons in a 32-week period completed prior to birth. This review discusses our current understanding of Mammalian nephrogenesis: the contributing cell types and the regulatory processes at play. A conceptual developmental framework has emerged for the mouse Kidney. This framework is now guiding studies of human Kidney development enabled in part by in vitro systems of pluripotent stem cell-seeded nephrogenesis. A near future goal will be to translate our developmental knowledge-base to the productive engineering of new Kidney structures for regenerative medicine.
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identification of a multipotent self renewing stromal progenitor population during Mammalian Kidney organogenesis
Stem cell reports, 2014Co-Authors: Michaela A Krautzberger, Natalie Naiman, Jessica Liao, Joshua W Mugford, Andrew P Mcmahon, Akio KobayashiAbstract:The Mammalian Kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic functional unit of the Kidney. However, the cellular mechanisms establishing stromal tissues are less clear. We demonstrate that the Foxd1-expressing cortical stroma represents a distinct multipotent self-renewing progenitor population that gives rise to stromal tissues of the interstitium, mesangium, and pericytes throughout Kidney organogenesis. Fate map analysis of Foxd1-expressing cells demonstrates that a small subset of these cells contributes to Six2-expressing cells at the early stage of Kidney outgrowth. Thereafter, there appears to be a strict nephron and stromal lineage boundary derived from Six2-expressing and Foxd1-expressing cell types, respectively. Taken together, our observations suggest that distinct multipotent self-renewing progenitor populations coordinate cellular differentiation of the nephron epithelium and renal stroma during Mammalian Kidney organogenesis.
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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.
Akio Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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identification of a multipotent self renewing stromal progenitor population during Mammalian Kidney organogenesis
Stem cell reports, 2014Co-Authors: Michaela A Krautzberger, Natalie Naiman, Jessica Liao, Joshua W Mugford, Andrew P Mcmahon, Akio KobayashiAbstract:The Mammalian Kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic functional unit of the Kidney. However, the cellular mechanisms establishing stromal tissues are less clear. We demonstrate that the Foxd1-expressing cortical stroma represents a distinct multipotent self-renewing progenitor population that gives rise to stromal tissues of the interstitium, mesangium, and pericytes throughout Kidney organogenesis. Fate map analysis of Foxd1-expressing cells demonstrates that a small subset of these cells contributes to Six2-expressing cells at the early stage of Kidney outgrowth. Thereafter, there appears to be a strict nephron and stromal lineage boundary derived from Six2-expressing and Foxd1-expressing cell types, respectively. Taken together, our observations suggest that distinct multipotent self-renewing progenitor populations coordinate cellular differentiation of the nephron epithelium and renal stroma during Mammalian Kidney organogenesis.
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a wnt7b dependent pathway regulates the orientation of epithelial cell division and establishes the cortico medullary axis of the Mammalian Kidney
Development, 2009Co-Authors: Thomas J Carroll, Akio Kobayashi, Jay Rajagopal, Qun Ren, Andrew P McmahonAbstract:The Mammalian Kidney is organized into a cortex where primary filtration occurs, and a medullary region composed of elongated tubular epithelia where urine is concentrated. We show that the cortico-medullary axis of Kidney organization and function is regulated by Wnt7b signaling. The future collecting duct network specifically expresses Wnt7b. In the absence of Wnt7b, cortical epithelial development is normal but the medullary zone fails to form and urine fails to be concentrated normally. The analysis of cell division planes in the collecting duct epithelium of the emerging medullary zone indicates a bias along the longitudinal axis of the epithelium. By contrast, in Wnt7b mutants, cell division planes in this population are biased along the radial axis, suggesting that Wnt7b-mediated regulation of the cell cleavage plane contributes to the establishment of a cortico-medullary axis. The removal of β-catenin from the underlying Wnt-responsive interstitium phenocopies the medullary deficiency of Wnt7b mutants, suggesting a paracrine role for Wnt7b action through the canonical Wnt pathway. Wnt7b signaling is also essential for the coordinated growth of the loop of Henle, a medullary extension of the nephron that elongates in parallel to the collecting duct epithelium. These findings demonstrate that Wnt7b is a key regulator of the tissue architecture that establishes a functional physiologically active Mammalian Kidney.
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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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intrinsic epithelial cells repair the Kidney after injury
Cell Stem Cell, 2008Co-Authors: Enjami D Humphreys, Todd M Valerius, Joshua W Mugford, Savuth Soeung, Jeremy S Duffield, Andrew P Mcmaho, Joseph V Onventre, Akio KobayashiAbstract:Understanding the mechanisms of nephron repair is critical for the design of new therapeutic approaches to treat Kidney disease. The Kidney can repair after even a severe insult, but whether adult stem or progenitor cells contribute to epithelial renewal after injury and the cellular origin of regenerating cells remain controversial. Using genetic fate-mapping techniques, we generated transgenic mice in which 94%-95% of tubular epithelial cells, but no interstitial cells, were labeled with either beta-galactosidase (lacZ) or red fluorescent protein (RFP). Two days after ischemia-reperfusion injury (IRI), 50.5% of outer medullary epithelial cells coexpress Ki67 and RFP, indicating that differentiated epithelial cells that survived injury undergo proliferative expansion. After repair was complete, 66.9% of epithelial cells had incorporated BrdU, compared to only 3.5% of cells in the uninjured Kidney. Despite this extensive cell proliferation, no dilution of either cell-fate marker was observed after repair. These results indicate that regeneration by surviving tubular epithelial cells is the predominant mechanism of repair after ischemic tubular injury in the adult Mammalian Kidney.
Todd M Valerius - One of the best experts on this subject based on the ideXlab platform.
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six2 and wnt regulate self renewal and commitment of nephron progenitors through shared gene regulatory networks
Developmental Cell, 2012Co-Authors: Todd M Valerius, Jooseop Park, Lori L Obrien, Eunah Chung, Jin Jin Guo, Jr Gang Cheng, Jill A Mcmahon, Wing Hung WongAbstract:A balance between Six2-dependent self-renewal and canonical Wnt signaling-directed commitment regulates Mammalian nephrogenesis. Intersectional studies using chromatin immunoprecipitation and transcriptional profiling identified direct target genes shared by each pathway within nephron progenitors. Wnt4 and Fgf8 are essential for progenitor commitment; cis-regulatory modules flanking each gene are cobound by Six2 and β-catenin and are dependent on conserved Lef/Tcf binding sites for activity. In vitro and in vivo analyses suggest that Six2 and Lef/Tcf factors form a regulatory complex that promotes progenitor maintenance while entry of β-catenin into this complex promotes nephrogenesis. Alternative transcriptional responses associated with Six2 and β-catenin cobinding events occur through non-Lef/Tcf DNA binding mechanisms, highlighting the regulatory complexity downstream of Wnt signaling in the developing Mammalian Kidney.
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dicer regulates the development of nephrogenic and ureteric compartments in the Mammalian Kidney
Kidney International, 2011Co-Authors: Vidya K Nagalakshmi, Todd M Valerius, Qun Ren, Margaret M Pugh, Andrew P McmahonAbstract:MicroRNAs (miRNAs) are a large and growing class of small, non-coding, regulatory RNAs that control gene expression predominantly at the post-transcriptional level. The production of most functional miRNAs depends on the enzymatic activity of Dicer, an RNase III class enzyme. To address the potential action of Dicer-dependent miRNAs in Mammalian Kidney development, we conditionally ablated Dicer function within cells of nephron lineage and the ureteric bud-derived collecting duct system. Six2Cre-mediated removal of Dicer activity from the progenitors of the nephron epithelium led to elevated apoptosis and premature termination of nephrogenesis. Thus, Dicer action is important for maintaining the viability of this critical self-renewing progenitor pool and, consequently, development of a normal nephron complement. HoxB7Cre-mediated removal of Dicer function from the ureteric bud epithelium led to the development of renal cysts. This was preceded by excessive cell proliferation and apoptosis, and accompanied by disrupted ciliogenesis within the ureteric bud epithelium. Dicer removal also disrupted branching morphogenesis with the phenotype correlating with downregulation of Wnt11 and c-Ret expression at ureteric tips. Thus Dicer, and by inference Dicer-dependent miRNA activity, have distinct regulatory roles within different components of the developing mouse Kidney. Furthermore, an understanding of miRNA action may provide new insights into the etiology and pathogenesis of renal cyst-based Kidney disease.
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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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intrinsic epithelial cells repair the Kidney after injury
Cell Stem Cell, 2008Co-Authors: Enjami D Humphreys, Todd M Valerius, Joshua W Mugford, Savuth Soeung, Jeremy S Duffield, Andrew P Mcmaho, Joseph V Onventre, Akio KobayashiAbstract:Understanding the mechanisms of nephron repair is critical for the design of new therapeutic approaches to treat Kidney disease. The Kidney can repair after even a severe insult, but whether adult stem or progenitor cells contribute to epithelial renewal after injury and the cellular origin of regenerating cells remain controversial. Using genetic fate-mapping techniques, we generated transgenic mice in which 94%-95% of tubular epithelial cells, but no interstitial cells, were labeled with either beta-galactosidase (lacZ) or red fluorescent protein (RFP). Two days after ischemia-reperfusion injury (IRI), 50.5% of outer medullary epithelial cells coexpress Ki67 and RFP, indicating that differentiated epithelial cells that survived injury undergo proliferative expansion. After repair was complete, 66.9% of epithelial cells had incorporated BrdU, compared to only 3.5% of cells in the uninjured Kidney. Despite this extensive cell proliferation, no dilution of either cell-fate marker was observed after repair. These results indicate that regeneration by surviving tubular epithelial cells is the predominant mechanism of repair after ischemic tubular injury in the adult Mammalian Kidney.
Thomas L Pannabecker - One of the best experts on this subject based on the ideXlab platform.
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comparative physiology and architecture associated with the Mammalian urine concentrating mechanism role of inner medullary water and urea transport pathways in the rodent medulla
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2013Co-Authors: Thomas L PannabeckerAbstract:Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the Mammalian Kidney. This review focuses on the tubular transport p...
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urine concentrating mechanism in the inner medulla of the Mammalian Kidney role of three dimensional architecture
Acta Physiologica, 2011Co-Authors: William H Dantzler, Thomas L Pannabecker, Anita T Layton, Harold E LaytonAbstract:The urine concentrating mechanism in the Mammalian renal inner medulla (IM) is not understood, although it is generally considered to involve countercurrent flows in tubules and blood vessels. A possible role for the three-dimensional relationships of these tubules and vessels in the concentrating process is suggested by recent reconstructions from serial sections labelled with antibodies to tubular and vascular proteins and mathematical models based on these studies. The reconstructions revealed that the lower 60% of each descending thin limb (DTL) of Henle’s loops lacks water channels (aquaporin-1) and osmotic water permeability and ascending thin limbs (ATLs) begin with a prebend segment of constant length. In the outer zone of the IM (i) clusters of coalescing collecting ducts (CDs) form organizing motif for loops of Henle and vasa recta; (ii) DTLs and descending vasa recta (DVR) are arrayed outside CD clusters, whereas ATLs and ascending vasa recta (AVR) are uniformly distributed inside and outside clusters; (iii) within CD clusters, interstitial nodal spaces are formed by a CD on one side, AVR on two sides, and an ATL on the fourth side. These spaces may function as mixing chambers for urea from CDs and NaCl from ATLs. In the inner zone of the IM, cluster organization disappears and half of Henle’s loops have broad lateral bends wrapped around terminal CDs. Mathematical models based on these findings and involving solute mixing in the interstitial spaces can produce urine slightly more concentrated than that of a moderately antidiuretic rat but no higher.
Paul Goodyer - One of the best experts on this subject based on the ideXlab platform.
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wilms tumor suppressor wt1 suppresses epigenetic silencing of the β catenin gene
Journal of Biological Chemistry, 2015Co-Authors: Murielle M Akpa, Diana M Iglesias, Paul Goodyer, Lee Lee Chu, Marta Cybulsky, Cristina BraviAbstract:Abstract The Mammalian Kidney is derived from progenitor cells in intermediate mesoderm. During embryogenesis, progenitor cells expressing the Wilms tumor suppressor gene, WT1, are induced to differentiate in response to WNT signals from the ureteric bud. In hereditary Wilms tumors, clonal loss of WT1 precludes the β-catenin pathway response and leads to precancerous nephrogenic rests. We hypothesized that WT1 normally primes progenitor cells for differentiation by suppressing the enhancer of zeste2 gene (EZH2), involved in epigenetic silencing of differentiation genes. In human amniotic fluid-derived mesenchymal stem cells, we show that exogenous WT1B represses EZH2 transcription. This leads to a dramatic decrease in the repressive lysine 27 trimethylation mark on histone H3 that silences β-catenin gene expression. As a result, amniotic fluid mesenchymal stem cells acquire responsiveness to WNT9b and increase expression of genes that mark the onset of nephron differentiation. Our observations suggest that biallelic loss of WT1 sustains the inhibitory histone methylation state that characterizes Wilms tumors.
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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.
