scholarly journals Ret signaling in ureteric bud epithelial cells controls cell movements, cell clustering and bud formation

Development ◽  
2021 ◽  
Vol 148 (9) ◽  
Author(s):  
Adam Packard ◽  
William H. Klein ◽  
Frank Costantini
Keyword(s):  
Kidney Development ◽  
Branching Morphogenesis ◽  
Ureteric Bud ◽  
Cellular Mechanisms ◽  
Cell Behaviors ◽  
Genetic Ablation ◽  
Cell Clustering ◽  
Seeking Behavior ◽  
Dependent Cell ◽  
Tip Cells

ABSTRACT Ret signaling promotes branching morphogenesis during kidney development, but the underlying cellular mechanisms remain unclear. While Ret-expressing progenitor cells proliferate at the ureteric bud tips, some of these cells exit the tips to generate the elongating collecting ducts, and in the process turn off Ret. Genetic ablation of Ret in tip cells promotes their exit, suggesting that Ret is required for cell rearrangements that maintain the tip compartments. Here, we examine the behaviors of ureteric bud cells that are genetically forced to maintain Ret expression. These cells move to the nascent tips, and remain there during many cycles of branching; this tip-seeking behavior may require positional signals from the mesenchyme, as it occurs in whole kidneys but not in epithelial ureteric bud organoids. In organoids, cells forced to express Ret display a striking self-organizing behavior, attracting each other to form dense clusters within the epithelium, which then evaginate to form new buds. The ability of forced Ret expression to promote these events suggests that similar Ret-dependent cell behaviors play an important role in normal branching morphogenesis.

scholarly journals Involvement of Laminin Binding Integrins and Laminin-5 in Branching Morphogenesis of the Ureteric Bud during Kidney Development

2001 ◽  
Vol 238 (2) ◽  
pp. 289-302 ◽  
Author(s):  
Roy Zent ◽  
Kevin T. Bush ◽  
Martin L. Pohl ◽  
Vito Quaranta ◽  
Naohiko Koshikawa ◽  
...  
Keyword(s):  
Kidney Development ◽  
Branching Morphogenesis ◽  
Ureteric Bud ◽  
Laminin 5 ◽  
Laminin Binding

scholarly journals Generation of kidney ureteric bud and collecting duct organoids that recapitulate kidney branching morphogenesis

2020 ◽  
Author(s):  
Zipeng Zeng ◽  
Biao Huang ◽  
Riana K. Parvez ◽  
Yidan Li ◽  
Jyunhao Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Kidney Development ◽  
De Novo ◽  
Collecting Duct ◽  
Branching Morphogenesis ◽  
Ureteric Bud ◽  
Primary Mouse ◽  
Collecting System

AbstractKidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from pluripotent human stem cells. UB organoids differentiate into CD organoids in vitro, with differentiated cell types adopting spatial assemblies reflective of the adult kidney collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Combining efficient gene editing with the UB organoid model will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting system.One sentence summaryCollecting duct organoids derived from primary mouse and human ureteric bud progenitor cells and human pluripotent stem cells provide an in vitro platform for genetic dissection of development, regeneration and diseases of the mammalian collecting system.

scholarly journals Branching morphogenesis in the developing kidney is not impacted by nephron formation or integration

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Kieran M Short ◽  
Alexander N Combes ◽  
Valerie Lisnyak ◽  
James G Lefevre ◽  
Lynelle K Jones ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Kidney Development ◽  
Developmental Process ◽  
Branching Morphogenesis ◽  
Ureteric Bud ◽  
Collecting Ducts ◽  
Developing Kidney ◽  
Developmental Feature ◽  
Nephron Progenitor ◽  
The Impact

Branching morphogenesis of the ureteric bud is integral to kidney development; establishing the collecting ducts of the adult organ and driving organ expansion via peripheral interactions with nephron progenitor cells. A recent study suggested that termination of tip branching within the developing kidney involved stochastic exhaustion in response to nephron formation, with such a termination event representing a unifying developmental process evident in many organs. To examine this possibility, we have profiled the impact of nephron formation and maturation on elaboration of the ureteric bud during mouse kidney development. We find a distinct absence of random branch termination events within the kidney or evidence that nephrogenesis impacts the branching program or cell proliferation in either tip or progenitor cell niches. Instead, organogenesis proceeds in a manner indifferent to the development of these structures. Hence, stochastic cessation of branching is not a unifying developmental feature in all branching organs.

scholarly journals Hoxa11andHoxd11regulate branching morphogenesis of the ureteric bud in the developing kidney

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 2153-2161 ◽  
Author(s):  
Larry T. Patterson ◽  
Martina Pembaur ◽  
S. Steven Potter
Keyword(s):  
Gene Expression ◽  
Kidney Development ◽  
Growth Failure ◽  
Immunohistochemical Analysis ◽  
Branching Morphogenesis ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Metanephric Kidney ◽  
Normal Gene ◽  
Ureteric Buds

Hoxa11 and Hoxd11 are functionally redundant during kidney development. Mice with homozygous null mutation of either gene have normal kidneys, but double mutants have rudimentary, or in extreme cases, absent kidneys. We have examined the mechanism for renal growth failure in this mouse model and find defects in ureteric bud branching morphogenesis. The ureteric buds are either unbranched or have an atypical pattern characterized by lack of terminal branches in the midventral renal cortex. The mutant embryos show that Hoxa11 and Hoxd11 control development of a dorsoventral renal axis. By immunohistochemical analysis, Hoxa11 expression is restricted to the early metanephric mesenchyme, which induces ureteric bud formation and branching. It is not found in the ureteric bud. This suggests that the branching defect had been caused by failure of mesenchyme to epithelium signaling. In situ hybridizations with Wnt7b, a marker of the metanephric kidney, show that the branching defect was not simply the result of homeotic transformation of metanephros to mesonephros. Absent Bf2 and Gdnf expression in the midventral mesenchyme, findings that could by themselves account for branching defects, shows that Hoxa11 and Hoxd11 are necessary for normal gene expression in the ventral mesenchyme. Attenuation of normal gene expression along with the absence of a detectable proliferative or apoptotic change in the mutants show that one function of Hoxa11 and Hoxd11 in the developing renal mesenchyme is to regulate differentiation necessary for mesenchymal-epithelial reciprocal inductive interactions.

Dynamic modeling of branching morphogenesis of ureteric bud in early kidney development

2009 ◽  
Vol 259 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Tsuyoshi Hirashima ◽  
Yoh Iwasa ◽  
Yoshihiro Morishita
Keyword(s):  
Dynamic Modeling ◽  
Kidney Development ◽  
Branching Morphogenesis ◽  
Ureteric Bud

scholarly journals Generation of patterned kidney organoids that recapitulate the adult kidney collecting duct system from expandable ureteric bud progenitors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zipeng Zeng ◽  
Biao Huang ◽  
Riana K. Parvez ◽  
Yidan Li ◽  
Jyunhao Chen ◽  
...  
Keyword(s):  
Kidney Development ◽  
De Novo ◽  
Collecting Duct ◽  
Model Development ◽  
Branching Morphogenesis ◽  
Duct System ◽  
Ureteric Bud ◽  
Defined Culture ◽  
Kidney Organoids

AbstractCurrent kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney’s collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.

scholarly journals Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development

2018 ◽  
Vol 29 (12) ◽  
pp. 2795-2808 ◽  
Author(s):  
Shintaro Ide ◽  
Gal Finer ◽  
Yoshiro Maezawa ◽  
Tuncer Onay ◽  
Tomokazu Souma ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Renal Dysplasia ◽  
Branching Morphogenesis ◽  
Mrna Levels ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Renal Hypodysplasia ◽  
Cap Mesenchyme

BackgroundThe mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.MethodsUsing a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of the Tcf21 gene, mice with stromal mesenchyme–specific Tcf21 deletion, and mice with cap mesenchyme–specific Tcf21 deletion.ResultsGermline deletion of Tcf21 leads to impaired ureteric bud branching and is accompanied by downregulated expression of Gdnf-Ret-Wnt11, a key pathway required for branching morphogenesis. Selective removal of Tcf21 from the renal stroma is also associated with attenuation of the Gdnf signaling axis and leads to a defect in ureteric bud branching, a paucity of collecting ducts, and a defect in urine concentration capacity. In contrast, deletion of Tcf21 from the cap mesenchyme leads to abnormal glomerulogenesis and massive proteinuria, but no downregulation of Gdnf-Ret-Wnt11 or obvious defect in branching.ConclusionsOur findings indicate that Tcf21 has distinct roles in the cap mesenchyme and stromal mesenchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis.

scholarly journals Identification of pleiotrophin as a mesenchymal factor involved in ureteric bud branching morphogenesis

Development ◽  
2001 ◽  
Vol 128 (17) ◽  
pp. 3283-3293 ◽  
Author(s):  
Hiroyuki Sakurai ◽  
Kevin T. Bush ◽  
Sanjay K. Nigam
Keyword(s):  
Cell Line ◽  
Conditioned Medium ◽  
Kidney Development ◽  
Egf Receptor ◽  
Branching Morphogenesis ◽  
Metanephric Mesenchyme ◽  
Receptor Ligands ◽  
Ureteric Bud ◽  
Apparent Homogeneity ◽  
Mesenchyme Cell

Branching morphogenesis is central to epithelial organogenesis. In the developing kidney, the epithelial ureteric bud invades the metanephric mesenchyme, which directs the ureteric bud to undergo repeated branching. A soluble factor(s) in the conditioned medium of a metanephric mesenchyme cell line is essential for multiple branching morphogenesis of the isolated ureteric bud. The identity of this factor had proved elusive, but it appeared distinct from factors such as HGF and EGF receptor ligands that have been previously implicated in branching morphogenesis of mature epithelial cell lines. Using sequential column chromatography, we have now purified to apparent homogeneity an 18 kDa protein, pleiotrophin, from the conditioned medium of a metanephric mesenchyme cell line that induces isolated ureteric bud branching morphogenesis in the presence of glial cell-derived neurotrophic factor. Pleiotrophin alone was also found to induce the formation of branching tubules in an immortalized ureteric bud cell line cultured three-dimensionally in an extracellular matrix gel. Consistent with an important role in ureteric bud morphogenesis during kidney development, pleiotrophin was found to localize to the basement membrane of the developing ureteric bud in the embryonic kidney. We suggest that pleiotrophin could act as a key mesenchymally derived factor regulating branching morphogenesis of the ureteric bud and perhaps other embryonic epithelial structures.

Matrix metalloproteinases and their inhibitors regulate in vitro ureteric bud branching morphogenesis

2000 ◽  
Vol 279 (5) ◽  
pp. F891-F900 ◽  
Author(s):  
Martin Pohl ◽  
Hiroyuki Sakurai ◽  
Kevin T. Bush ◽  
Sanjay K. Nigam
Keyword(s):  
Conditioned Medium ◽  
Kidney Development ◽  
Gelatin Zymography ◽  
Branching Morphogenesis ◽  
Complex Model ◽  
Northern Analysis ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Direct Role

Mammalian kidney development is initiated by the mutual interaction between embryonic metanephric mesenchyme (MM) and the ureteric bud (UB), leading to tightly controlled UB branching morphogenesis. In a three-dimensional cell culture model, which employs MM cell-derived conditioned medium (BSN-CM) to induce UB cell branching morphogenesis in extracellular matrix (ECM) gels (Sakurai H, Barros EJ, Tsukamoto T, Barasch J, and Nigam SK. Proc Natl Acad Sci USA 94: 6279–6284, 1997), branching morphogenesis was inhibited by both chemical agents (ilomastat and 1,10-orthophenanthroline) and a physiological protein factor [tissue inhibitor of metalloproteinases (TIMP)-2], known to act as matrix metalloproteinase (MMP) inhibitors. In addition, UB branching was inhibited in isolated UB culture (Qiao J, Sakurai H, and Nigam SK. Proc Natl Acad Sci USA96: 7330–7335, 1999) by TIMP-2 and ilomastat, suggesting a direct role for MMPs in UB branching. Gelatin zymography and enzymatic measurement of MMP activity revealed that MMPs could originate from at least three different sources: the conditioned medium, the ECM, and the UB cells themselves. In the UB cells, transcription of several MMPs [gelatinase A (MMP2) and B (MMP9), stromelysin (MMP3), MT1-MMP] and TIMPs was altered by BSN-CM and changed as more complex branching structures formed. The ECM appeared to serve as both a reservoir for MMPs and modulated their expression because different ECM compositions altered the total MMP activity as well as specific subsets of MMPs expressed by the UB cells (as determined by zymography and Northern analysis). In the context of UB branching morphogenesis during kidney development, our data suggest a complex model in which soluble factors produced by the MM, in the context of specific ECM components, modulate the expression of specific subsets of MMPs and TIMPs in the UB, which alter as structures develop and the matrix environment changes. This suggests distinct roles for different subsets of MMPs and their inhibitors during different phases of branching morphogenesis.

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