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Frank Costantini - One of the best experts on this subject based on the ideXlab platform.
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chapter 4 ret signaling in Ureteric Bud formation and branching
Kidney Development Disease Repair and Regeneration, 2016Co-Authors: Frank CostantiniAbstract:The Ureteric Bud (UB) is an epithelial tube that arises from the nephric duct and branches repetitively to give rise to the renal collecting duct system while also generating inductive signals that promote nephrogenesis by surrounding metanephric mesenchyme (MM) cells. Defects in UB growth and branching can lead to renal agenesis, hypodysplasia, and other congenital abnormalities of the kidney and urinary tract. A key signal that promotes UB morphogenesis is glial cell-derived neurotrophic factor (GDNF), a protein secreted by MM cells that signals to UB cells via the rearranged in transformation (RET) receptor tyrosine kinase and the coreceptor GDNF family receptor α1. This chapter presents a short introduction to the process of UB growth and branching and then focuses on the effects of RET pathway mutations on kidney development in mice and humans, the regulation of Gdnf and Ret expression, the signaling pathways and genes that act downstream of RET, cooperation between GDNF and fibroblast growth factor signaling, the role of RET in patterning the UB, and the cellular behaviors by which RET may influence UB formation and branching morphogenesis.
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Chapter 4 – RET Signaling in Ureteric Bud Formation and Branching
Kidney Development Disease Repair and Regeneration, 2016Co-Authors: Frank CostantiniAbstract:The Ureteric Bud (UB) is an epithelial tube that arises from the nephric duct and branches repetitively to give rise to the renal collecting duct system while also generating inductive signals that promote nephrogenesis by surrounding metanephric mesenchyme (MM) cells. Defects in UB growth and branching can lead to renal agenesis, hypodysplasia, and other congenital abnormalities of the kidney and urinary tract. A key signal that promotes UB morphogenesis is glial cell-derived neurotrophic factor (GDNF), a protein secreted by MM cells that signals to UB cells via the rearranged in transformation (RET) receptor tyrosine kinase and the coreceptor GDNF family receptor α1. This chapter presents a short introduction to the process of UB growth and branching and then focuses on the effects of RET pathway mutations on kidney development in mice and humans, the regulation of Gdnf and Ret expression, the signaling pathways and genes that act downstream of RET, cooperation between GDNF and fibroblast growth factor signaling, the role of RET in patterning the UB, and the cellular behaviors by which RET may influence UB formation and branching morphogenesis.
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The transcription factors Etv4 and Etv5 mediate formation of the Ureteric Bud tip domain during kidney development
Development (Cambridge England), 2010Co-Authors: Satu Kuure, Xuan Chi, Frank CostantiniAbstract:Signaling by the Ret receptor tyrosine kinase promotes cell movements in the Wolffian duct that give rise to the first Ureteric Bud tip, initiating kidney development. Although the ETS transcription factors Etv4 and Etv5 are known to be required for mouse kidney development and to act downstream of Ret, their specific functions are unclear. Here, we examine their role by analyzing the ability of Etv4 Etv5 compound mutant cells to contribute to chimeric kidneys. Etv4−/−;Etv5+/− cells show a limited distribution in the caudal Wolffian duct and Ureteric Bud, similar to Ret−/− cells, revealing a cell-autonomous role for Etv4 and Etv5 in the cell rearrangements promoted by Ret. By contrast, Etv4−/−;Etv5−/− cells display more severe developmental limitations, suggesting a broad role for Etv4 and Etv5 downstream of multiple signals, which are together important for Wolffian duct and Ureteric Bud morphogenesis.
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A transgenic mouse that reveals cell shape and arrangement during Ureteric Bud branching
Genesis (New York N.Y. : 2000), 2009Co-Authors: Xuan Chi, Deborah Hyink, Anna-katerina Hadjantonakis, Frank CostantiniAbstract:Understanding the cellular events that underlie epithelial morphogenesis is a key problem in developmental biology. Here, we describe a new transgenic mouse line that makes it possible to visualize individual cells specifically in the Wolffian duct and Ureteric Bud, the epithelial structures that give rise to the collecting system of the kidney. myr-Venus, a membrane-associated form of the fluorescent protein Venus, was expressed in the Ureteric Bud lineage under the control of the Hoxb7 promoter. In Hoxb7/myr-Venus mice, the outlines of all Wolffian duct and Ureteric Bud epithelial cells are strongly labeled at all stages of urogenital development, allowing the shapes and arrangements of individual cells to be readily observed by confocal microscopy of freshly excised or cultured kidneys. This strain should be extremely useful for studies of cell behavior during Ureteric Bud branching morphogenesis in wild type and mutant mouse lines.
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Novel Regulators of Kidney Development from the Tips of the Ureteric Bud
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: Kai M. Schmidt-ott, Frank Costantini, Kiyoshi Mori, Jun Yang, Xia Chen, Howard Wang, Neal Paragas, Mario SchifferAbstract:Mammalian nephrogenesis depends on the interaction between the Ureteric Bud and the metanephric mesenchyme. As the Ureteric Bud undergoes branching and segmentation, the stalks differentiate into the collecting system of the mature kidney, while the tip cells interact with the adjacent cells of the metanephric mesenchyme, inducing their conversion into nephrons. This induction is mediated by secreted factors. For identifying novel mediators, the tips of the Ureteric tree were isolated and microarray analyses were performed using manually refined, multistep gene ontology annotations. For identifying conserved factors, two databases were developed, one from mouse E12.5 and one from rat E13.5 Ureteric Buds. The overlap of mouse and rat data sets yielded 20 different transcripts that were enriched in the Ureteric Bud compared with metanephric mesenchyme and predicted to code for secreted proteins. Real-time reverse transcriptase-PCR and in situ hybridization confirmed these identifications. One of the genes that was highly specific to the Ureteric Bud tip was cytokine-like factor 1 (CLF-1). Recombinant CLF-1 in complex with its physiologic ligand, cardiotrophin-like cytokine (CLC), triggered phosphorylation of signal transducer and activator of transcription 3 in mesenchyme, a pathway characteristic of mesenchymal-to-epithelial conversion. Indeed, when applied to isolated rat metanephric mesenchyme, CLF-1/CLC (3 nM) induced mature nephron structures expressing glomerular and tubular markers. These results underline the power of this first comprehensive gene expression analysis of the Ureteric Bud tip to identify bioactive molecules.
Jamie A. Davies - One of the best experts on this subject based on the ideXlab platform.
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differentiation of a contractile ureter like tissue from embryonic stem cell derived Ureteric Bud and ex fetu mesenchyme
Journal of The American Society of Nephrology, 2020Co-Authors: May Sallam, Anwar Azad Palakkan, Christopher G Mills, Julia Tarnick, Mona Elhendawi, Lorna Marson, Jamie A. DaviesAbstract:BACKGROUND There is intense interest in replacing kidneys from stem cells. It is now possible to produce, from embryonic or induced pluripotent stem cells, kidney organoids that represent immature kidneys and display some physiologic functions. However, current techniques have not yet resulted in renal tissue with a ureter, which would be needed for engineered kidneys to be clinically useful. METHODS We used a published sequence of growth factors and drugs to induce mouse embryonic stem cells to differentiate into Ureteric Bud tissue. We characterized isolated engineered Ureteric Buds differentiated from embryonic stem cells in three-dimensional culture and grafted them into ex fetu mouse kidney rudiments. RESULTS Engineered Ureteric Buds branched in three-dimensional culture and expressed Hoxb7, a transcription factor that is part of a developmental regulatory system and a Ureteric Bud marker. When grafted into the cortex of ex fetu kidney rudiments, engineered Ureteric Buds branched and induced nephron formation; when grafted into peri-Wolffian mesenchyme, still attached to a kidney rudiment or in isolation, they did not branch but instead differentiated into multilayer ureter-like epithelia displaying robust expression of the urothelial marker uroplakin. This engineered Ureteric Bud tissue also organized the mesenchyme into smooth muscle that spontaneously contracted, with a period a little slower than that of natural Ureteric peristalsis. CONCLUSIONS Mouse embryonic stem cells can be differentiated into Ureteric Bud cells. Grafting those UB-like structures into peri-Wolffian mesenchyme of cultured kidney rudiments can induce production of urothelium and organize the mesenchyme to produce rhythmically contracting smooth muscle layers. This development may represent a significant step toward the goal of renal regeneration.
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dact2 is expressed in the developing Ureteric Bud collecting duct system of the kidney and controls morphogenetic behavior of collecting duct cells
American Journal of Physiology-renal Physiology, 2010Co-Authors: Wen-chin Lee, Melinda T. Hough, Weijia Liu, Robert Ekiert, Nils O. Lindström, Peter Hohenstein, Jamie A. DaviesAbstract:The overall pattern of the developing kidney is set in large part by the developing Ureteric Bud/collecting duct system, and dysgenesis of this system accounts for a variety of clinically significa...
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Dact2 is expressed in the developing Ureteric Bud/collecting duct system of the kidney and controls morphogenetic behavior of collecting duct cells
American Journal of Physiology-Renal Physiology, 2010Co-Authors: Wen-chin Lee, Melinda T. Hough, Weijia Liu, Robert Ekiert, Nils O. Lindström, Peter Hohenstein, Jamie A. DaviesAbstract:The overall pattern of the developing kidney is set in large part by the developing Ureteric Bud/collecting duct system, and dysgenesis of this system accounts for a variety of clinically significa...
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a role for microfilament based contraction in branching morphogenesis of the Ureteric Bud
Kidney International, 2005Co-Authors: Lydia Michael, Derina E Sweeney, Jamie A. DaviesAbstract:A role for microfilament-based contraction in branching morphogenesis of the Ureteric Bud . Background Branching morphogenesis of the Ureteric Bud/collecting duct epithelium is an important feature of kidney development. Recent work has identified many transcription factors and paracrine signaling molecules that regulate branching, but the physical mechanisms by which these signals act remain largely unknown. The actin cytoskeleton is a common component of mechanisms of morphogenesis. We have therefore studied the expression of, and requirement for actin filaments in the Ureteric Bud, a branching epithelium of the mammalian kidney. Methods Embryonic kidney rudiments were grown in organ culture. Actin expression in kidneys growing normally and those in which branching was inhibited was examined using labeled phalloidin. The morphogenetic effects of inhibiting actin organization and tension using cytochalasin D, butanedione monoxime, and Rho kinase ROCK inhibitors were assessed using immunofluorescence. Results F-actin is expressed particularly strongly in the apical domains of cells at the tips of branching Ureteric Bud, but this expression depends on the Bud actively growing and branching. Blocking the polymerization of actin using cytochalasin D inhibits Ureteric Bud branching reversibly, as does blocking myosin function using butadiene monoxime. Inhibiting the activation of ROCK, a known activator of myosin, with the drugs Y27632 or with H1152 inhibits the expression of strong actin bundles in the Ureteric Bud tips and inhibits Ureteric Bud branching without inhibiting other aspects of renal development. Conclusion The formation of tension-bearing actin-myosin complexes is essential for branching morphogenesis in the developing kidney.
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Pattern and regulation of cell proliferation during murine Ureteric Bud development
Journal of anatomy, 2004Co-Authors: Lydia Michael, Jamie A. DaviesAbstract:Branched epithelia determine the anatomy of many mammalian organs; understanding how they develop is therefore an important element of understanding organogenesis as a whole. In recent years, much progress has been made in identifying paracrine factors that regulate branching morphogenesis in many organs, but comparatively little attention has been paid to the mechanisms of morphogenesis that translate these signals into anatomical change. Localized cell proliferation is a potentially powerful mechanism for directing the growth of a developing system to produce a specific final morphology. We have examined the pattern of cell proliferation in the Ureteric Bud system of the embryonic murine metanephric kidneys developing in culture. We detect a zone of high proliferation at the site of the presumptive Ureteric Bud even before it emerges from the Wolffian duct and later, as Ureteric Bud morphogenesis continues, proliferation is localized mainly in the very tips of the branching epithelium. Blocking cell cycling using methotrexate inhibits Ureteric Bud emergence. The proliferative zone is present at Ureteric Bud tips only when they are undergoing active morphogenesis; if branching is inhibited either by treatment with natural negative regulators (TGF-beta) or with antagonists of natural positive regulators (GDNF, glycosaminoglycans) then proliferation at the tips falls back to levels characteristic of the stalks behind them. Our results suggest that localized proliferation is an important morphogenetic mechanism in kidney development.
Sanjay K. Nigam - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Ureteric Bud Outgrowth and the Consequences of Disrupted Development
Kidney Development Disease Repair and Regeneration, 2016Co-Authors: Kevin T. Bush, Sanjay K. NigamAbstract:Ureteric Bud (UB) outgrowth from the nephric (Wolffian) duct depends on a number of pathways, and its perturbation can cause diseases such as renal agenesis, vesicoureteral reflux, obstructive uropathy, and congenital anomalies of the kidney and urinary tract, which can result in chronic kidney disease. This chapter describes current knowledge on UB outgrowth during early kidney development based on in vivo and ex vivo (in vitro) rodent studies and applies it to human diseases. We describe how defining complex molecular interactions during early kidney induction is useful for understanding diseases relating to perturbed UB outgrowth.
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Relevance of Ureteric Bud development and branching to tissue engineering, regeneration and repair in acute and chronic kidney disease
Current opinion in organ transplantation, 2014Co-Authors: Kevin T. Bush, Gleb Martovetsky, Sanjay K. NigamAbstract:PURPOSE OF REVIEW: Chronic kidney disease is expected to continue to be a major health problem. There remains a huge shortage of donor tissues. A potential solution is to engineer a kidney-like tissue capable of performing differentiated renal functions. These functions are strikingly dependent upon appropriate three-dimensional relationships established during development, including those arising from branching morphogenesis of the Ureteric Bud. RECENT FINDINGS: The Ureteric Bud, an 'iterative tip-stalk generator' (ITSG) forming the scaffold around which the kidney is built, can be cultured and propagated ex vivo while retaining the capacity to induce and appropriately interact with nascent nephrons. Progress has been made toward construction of a Ureteric Bud from cells. SUMMARY: The myriad functions of the kidney are critically dependent upon its three-dimensional spatial architecture established by branching of the Ureteric Bud. Ureteric Bud branching morphogenesis can be recapitulated ex vivo; we discuss how this intrinsic property of the Ureteric Bud might be exploited for engineering of kidney-like tissues potentially useful for the treatment of chronic kidney disease, acute kidney injury, and/or other renal diseases.
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How Does the Ureteric Bud Branch
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Sanjay K. Nigam, Mita M. ShahAbstract:Many genes that modulate kidney development have been identified; however, the molecular interactions that direct arborization of the Ureteric Bud (UB) remain incompletely understood. This article discusses how "systems" approaches may shed light on the structure of the gene network during UB branching morphogenesis and the mechanisms involved in the formation of a branched collecting system from a straight epithelial tube in the context of a stage model. In vitro and genetic studies suggest that the stages seem to be governed by a conserved network of genes that establish a "tip-stalk generator"; these genes sustain iterative UB branching tubulogenesis through minimal alterations in the network architecture as a Budding system shifts to one that autocatalytically branches through Budding. The differential expression of stage-specific positive and inhibitory factors in the mesenchyme, likely presented in the context of heparan sulfate proteoglycans, and effector molecules in the epithelium seems to regulate advancement between stages; similar principles may apply to other branching epithelia such as the lung, salivary gland, pancreas, mammary gland, and prostate. Active mesenchymal interactions with the UB seem to govern vectorial arborization and tapering of the collecting system and its terminal differentiation. Cessation of branching correlates with induction of mesenchyme as well as local extracellular matrix changes. Perturbations of these mechanisms and/or single-nucleotide polymorphisms in genes regulating UB branching may predispose to a variety of renal diseases (e.g., hypertension and chronic kidney disease) by altering nephron number. Decentralization of the gene-protein interaction network may explain the relative paucity of branching phenotypes in mutant mice and in human disease.
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glial cell derived neurotrophic factor independent Ureteric Bud outgrowth from the wolffian duct
Journal of The American Society of Nephrology, 2007Co-Authors: Akito Maeshima, Hiroyuki Sakurai, Yohan Choi, Shinji Kitamura, James B. Tee, Duke A Vaughn, Sanjay K. NigamAbstract:The kidney collecting duct system and the ureter derive from the Ureteric Bud, an outgrowth of the Wolffian duct. It is generally believed that glial cell–derived neurotrophic factor (GDNF) plays a critical role in this earliest stage of kidney development, but 30 to 50% of knockout mice that lack
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Glial Cell–Derived Neurotrophic Factor–Independent Ureteric Bud Outgrowth from the Wolffian Duct
Journal of the American Society of Nephrology, 2007Co-Authors: Akito Maeshima, Hiroyuki Sakurai, Yohan Choi, Shinji Kitamura, A. Vaughn, James B. Tee, Sanjay K. NigamAbstract:The kidney collecting duct system and the ureter derive from the Ureteric Bud, an outgrowth of the Wolffian duct. It is generally believed that glial cell–derived neurotrophic factor (GDNF) plays a critical role in this earliest stage of kidney development, but 30 to 50% of knockout mice that lack
Carlton M Bates - One of the best experts on this subject based on the ideXlab platform.
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Loss of peri-Wolffian duct stromal Frs2α expression in mice leads to abnormal Ureteric Bud induction and vesicoureteral reflux
Pediatric Research, 2017Co-Authors: Deepti Narla, Stacey B Slagle, Caitlin M Schaefer, Daniel S Bushnell, Pawan Puri, Carlton M BatesAbstract:Background Fibroblast growth factor receptor 2 (Fgfr2) deletion from murine peri-Wolffian duct stroma (ST) results in aberrant Ureteric Bud induction, abnormal ureteral insertion into the bladder, and high rates of vesicoureteral reflux (VUR). It is unclear which receptor docking protein(s) is/are responsible for Fgfr2 actions in these tissues. We investigated whether the docking protein, fibroblast receptor substrate 2α ( Frs2α ), had a role in peri-Wolffian duct ST similar to Fgfr2. Methods We conditionally deleted Frs2α in peri-Wolffian duct ST with a Tbx18cre mouse line ( Frs2α ^ ST−/− ). We assessed for Ureteric induction defects and alterations in downstream targets mediating defects. We performed euthanized cystograms and assessed ureter–bladder junctions by three-dimensional (3D) reconstructions. Results Embryonic day (E) 11.5 Frs2α ^ ST−/− embryos had many displaced Ureteric Bud induction sites when compared with controls. E11.0 Frs2α ^ ST−/− embryos had decreased Bmp4 expression and signaling, which can cause abnormal Ureteric Bud induction. Postnatal day 1 (P1) and P30 Frs2α ^ ST−/− mice had higher VUR rates and grades vs. controls. Mutant refluxing ureters that inserted improperly into the bladder had shortened intravesicular tunnels (IVTs) when compared with controls Conclusion Frs2α ^ ST−/− embryos have aberrant Ureteric induction sites, improper ureteral insertion, shortened intravesicular lengths, and VUR. Induction site defects appear secondary to reduced Bmp4 expression, similar to Fgfr2 mutants.
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Loss of peri-Wolffian duct stromal Frs2α expression in mice leads to abnormal Ureteric Bud induction and vesicoureteral reflux
Pediatric research, 2017Co-Authors: Deepti Narla, Stacey B Slagle, Pawan Puri, Caitlin Schaefer, Daniel Bushnell, Carlton M BatesAbstract:Fibroblast growth factor receptor 2 (Fgfr2) deletion from murine peri-Wolffian duct stroma (ST) results in aberrant Ureteric Bud induction, abnormal ureteral insertion into the bladder, and high rates of vesicoureteral reflux (VUR). It is unclear which receptor docking protein(s) is/are responsible for Fgfr2 actions in these tissues. We investigated whether the docking protein, fibroblast receptor substrate 2α (Frs2α), had a role in peri-Wolffian duct ST similar to Fgfr2. We conditionally deleted Frs2α in peri-Wolffian duct ST with a Tbx18cre mouse line (Frs2αST−/−). We assessed for Ureteric induction defects and alterations in downstream targets mediating defects. We performed euthanized cystograms and assessed ureter–bladder junctions by three-dimensional (3D) reconstructions. Embryonic day (E) 11.5 Frs2αST−/− embryos had many displaced Ureteric Bud induction sites when compared with controls. E11.0 Frs2αST−/− embryos had decreased Bmp4 expression and signaling, which can cause abnormal Ureteric Bud induction. Postnatal day 1 (P1) and P30 Frs2αST−/− mice had higher VUR rates and grades vs. controls. Mutant refluxing ureters that inserted improperly into the bladder had shortened intravesicular tunnels (IVTs) when compared with controls Frs2αST−/− embryos have aberrant Ureteric induction sites, improper ureteral insertion, shortened intravesicular lengths, and VUR. Induction site defects appear secondary to reduced Bmp4 expression, similar to Fgfr2 mutants.
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Role of fibroblast growth factor receptors 1 and 2 in the Ureteric Bud.
Developmental biology, 2004Co-Authors: Haotian Zhao, Heather Kegg, Sandy Grady, Hoang Trang Truong, Michael L. Robinson, Michel Baum, Carlton M BatesAbstract:Fibroblast growth receptors (FGFRs) consist of four signaling family members. Mice with deletions of fgfr1 or fgfr2 are embryonic lethal prior to the onset of kidney development. To determine roles of FGFR1 and FGFR2 in the Ureteric Bud, we used a conditional targeting approach. First, we generated transgenic mice using the Hoxb7 promoter to drive cre recombinase and green fluorescent protein expression throughout Ureteric Bud tissue. We crossed Hoxb7creEGFP mice with mice carrying lox-p sites flanking critical regions of fgfr1 and/or fgfr2. Absence of fgfr1 from the Ureteric Bud (fgfr1UB−/−) results in no apparent renal abnormalities. In contrast, fgfr2UB−/− mice have very aberrant Ureteric Bud branching, thin Ureteric Bud stalks, and fewer Ureteric Bud tips. Fgfr2UB−/− Ureteric Bud tips also demonstrate inappropriate regions of apoptosis and reduced proliferation. The nephrogenic mesenchymal lineage in fgfr2UB−/− mice develops normal-appearing glomeruli and tubules, and only slightly fewer nephrons than controls. In contrast, fgfr2UB−/− kidneys have abnormally thickened subcapsular cortical stromal mesenchyme. Ultimately, fgfr2UB−/− adult kidneys are small and abnormally shaped or are hydronephrotic. Finally, there are no additional abnormalities in the fgfr1/2UB−/− kidneys versus the fgfr2UB−/− kidneys. In conclusion, FGFR2, but not FGFR1, appears crucial for Ureteric Bud branching morphogenesis and stromal mesenchyme patterning.
Odyssé Michos - One of the best experts on this subject based on the ideXlab platform.
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Luminal Mitosis Drives Epithelial Cell Dispersal within the Branching Ureteric Bud
Developmental cell, 2013Co-Authors: Adam Packard, Odyssé Michos, Paul Riccio, Kylie Georgas, Cristina Cebrian, Alexander N. Combes, Anna Ferrer-vaquer, Anna-katerina Hadjantonakis, Hui ZongAbstract:The Ureteric Bud is an epithelial tube that undergoes branching morphogenesis to form the renal collecting system. Although development of a normal kidney depends on proper Ureteric Bud morphogenesis, the cellular events underlying this process remain obscure. Here, we used time-lapse microscopy together with several genetic labeling methods to observe Ureteric Bud cell behaviors in developing mouse kidneys. We observed an unexpected cell behavior in the branching tips of the Ureteric Bud, which we term "mitosis-associated cell dispersal." Premitotic Ureteric tip cells delaminate from the epithelium and divide within the lumen; although one daughter cell retains a basal process, allowing it to reinsert into the epithelium at the site of origin, the other daughter cell reinserts at a position one to three cell diameters away. Given the high rate of cell division in Ureteric tips, this cellular behavior causes extensive epithelial cell rearrangements that may contribute to renal branching morphogenesis.
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Kidney development: from Ureteric Bud formation to branching morphogenesis.
Current opinion in genetics & development, 2009Co-Authors: Odyssé MichosAbstract:Epithelial branching morphogenesis is critical to the formation of various organs such as the vasculature, mammary glands, lungs, and kidneys in vertebrate embryos. One fascinating aspect of branching morphogenesis is to understand how a simple epithelial tube grows by reiterative branching to form a complex epithelial tree structure. Recent studies combining mouse genetics and chimeric analysis with live imaging have uncovered the molecular networks and interactions that govern kidney branching morphogenesis. This review focuses on Ureteric Bud (UB) formation and epithelial branching during kidney development. The invasion of the metanephric mesenchyme by the UB is a fundamental step toward establishing the cyto-architecture of the kidney and determining the number of nephrons, which form the filtration units of the adult kidney.
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Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate Ureteric Bud morphogenesis.
Developmental Cell, 2009Co-Authors: Xuan Chi, Odyssé Michos, Reena Shakya, Paul Riccio, Hideki Enomoto, Jonathan D. Licht, Naoya Asai, Masahide Takahashi, Nobutaka Ohgami, Masashi KatoAbstract:While the genetic control of renal branching morphogenesis has been extensively described, the cellular basis of this process remains obscure. GDNF/RET signaling is required for ureter and kidney development, and cells lacking Ret are excluded from the tips of the branching Ureteric Bud in chimeric kidneys. Here, we find that this exclusion results from earlier Ret-dependent cell rearrangements in the caudal Wolffian duct, which generate a specialized epithelial domain that later emerges as the tip of the primary Ureteric Bud. By juxtaposing cells with elevated or reduced RET activity, we find that Wolffian duct cells compete, based on RET signaling levels, to contribute to this domain. At the same time, the caudal Wolffian duct transiently converts from a simple to a pseudostratified epithelium, a process that does not require Ret. Thus, both Ret-dependent cell movements and Ret-independent changes in the Wolffian duct epithelium contribute to Ureteric Bud formation.
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reduction of bmp4 activity by gremlin 1 enables Ureteric Bud outgrowth and gdnf wnt11 feedback signalling during kidney branching morphogenesis
Development, 2007Co-Authors: Odyssé Michos, Seppo Vainio, Alexandre Goncalves, Javier Lopezrios, Eva Tiecke, Florence Naillat, Konstantin Beier, Antonella Galli, Rolf ZellerAbstract:Antagonists act to restrict and negatively modulate the activity of secreted signals during progression of embryogenesis. In mouse embryos lacking the extra-cellular BMP antagonist gremlin 1 ( Grem1 ), metanephric development is disrupted at the stage of initiating Ureteric Bud outgrowth. Treatment of mutant kidney rudiments in culture with recombinant gremlin 1 protein induces additional epithelial Buds and restores outgrowth and branching. All epithelial Buds express Wnt11, and Gdnf is significantly upregulated in the surrounding mesenchyme, indicating that epithelial-mesenchymal (e-m) feedback signalling is restored. In the wild type, Bmp4 is expressed by the mesenchyme enveloping the Wolffian duct and Ureteric Bud and Grem1 is upregulated in the mesenchyme around the nascent Ureteric Bud prior to initiation of its outgrowth. In agreement, BMP activity is reduced locally as revealed by lower levels of nuclear pSMAD protein in the mesenchyme. By contrast, in Grem1 -deficient kidney rudiments, pSMAD proteins are detected in many cell nuclei in the metanephric mesenchyme, indicative of excessive BMP signal transduction. Indeed, genetic lowering of BMP4 levels in Grem1 -deficient mouse embryos completely restores Ureteric Bud outgrowth and branching morphogenesis. The reduction of BMP4 levels in Grem1 mutant embryos enables normal progression of renal development and restores adult kidney morphology and functions. This study establishes that initiation of metanephric kidney development requires the reduction of BMP4 activity by the antagonist gremlin 1 in the mesenchyme, which in turn enables Ureteric Bud outgrowth and establishment of autoregulatory GDNF/WNT11 feedback signalling.
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Reduction of BMP4 activity by gremlin 1 enables Ureteric Bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis.
Development (Cambridge England), 2007Co-Authors: Odyssé Michos, Seppo Vainio, Alexandre Goncalves, Eva Tiecke, Florence Naillat, Konstantin Beier, Antonella Galli, Javier Lopez-rios, Rolf ZellerAbstract:Antagonists act to restrict and negatively modulate the activity of secreted signals during progression of embryogenesis. In mouse embryos lacking the extra-cellular BMP antagonist gremlin 1 ( Grem1 ), metanephric development is disrupted at the stage of initiating Ureteric Bud outgrowth. Treatment of mutant kidney rudiments in culture with recombinant gremlin 1 protein induces additional epithelial Buds and restores outgrowth and branching. All epithelial Buds express Wnt11, and Gdnf is significantly upregulated in the surrounding mesenchyme, indicating that epithelial-mesenchymal (e-m) feedback signalling is restored. In the wild type, Bmp4 is expressed by the mesenchyme enveloping the Wolffian duct and Ureteric Bud and Grem1 is upregulated in the mesenchyme around the nascent Ureteric Bud prior to initiation of its outgrowth. In agreement, BMP activity is reduced locally as revealed by lower levels of nuclear pSMAD protein in the mesenchyme. By contrast, in Grem1 -deficient kidney rudiments, pSMAD proteins are detected in many cell nuclei in the metanephric mesenchyme, indicative of excessive BMP signal transduction. Indeed, genetic lowering of BMP4 levels in Grem1 -deficient mouse embryos completely restores Ureteric Bud outgrowth and branching morphogenesis. The reduction of BMP4 levels in Grem1 mutant embryos enables normal progression of renal development and restores adult kidney morphology and functions. This study establishes that initiation of metanephric kidney development requires the reduction of BMP4 activity by the antagonist gremlin 1 in the mesenchyme, which in turn enables Ureteric Bud outgrowth and establishment of autoregulatory GDNF/WNT11 feedback signalling.
