Talk:Renal System Development

2010

Hs2st mediated kidney mesenchyme induction regulates early ureteric bud branching

Dev Biol. 2010 Mar 15;339(2):354-65. Epub 2010 Jan 6.

Shah MM, Sakurai H, Sweeney DE, Gallegos TF, Bush KT, Esko JD, Nigam SK.

Department of Medicine, University of California, San Diego, CA 92093-0693, USA.

Abstract

Heparan sulfate proteoglycans (HSPGs) are central modulators of developmental processes likely through their interaction with growth factors, such as GDNF, members of the FGF and TGFbeta superfamilies, EGF receptor ligands and HGF. Absence of the biosynthetic enzyme, heparan sulfate 2-O-sulfotransferase (Hs2st) leads to kidney agenesis. Using a novel combination of in vivo and in vitro approaches, we have reanalyzed the defect in morphogenesis of the Hs2st(-)(/)(-) kidney. Utilizing assays that separately model distinct stages of kidney branching morphogenesis, we found that the Hs2st(-/-) UB is able to undergo branching and induce mesenchymal-to-epithelial transformation when recombined with control MM, and the isolated Hs2st null UB is able to undergo branching morphogenesis in the presence of exogenous soluble pro-branching growth factors when embedded in an extracellular matrix, indicating that the UB is intrinsically competent. This is in contrast to the prevailing view that the defect underlying the renal agenesis phenotype is due to a primary role for 2-O sulfated HS in UB branching. Unexpectedly, the mutant MM was also fully capable of being induced in recombination experiments with wild-type tissue. Thus, both the mutant UB and mutant MM tissue appear competent in and of themselves, but the combination of mutant tissues fails in vivo and, as we show, in organ culture. We hypothesized a 2OS-dependent defect in the mutual inductive process, which could be on either the UB or MM side, since both progenitor tissues express Hs2st. In light of these observations, we specifically examined the role of the HS 2-O sulfation modification on the morphogenetic capacity of the UB and MM individually. We demonstrate that early UB branching morphogenesis is not primarily modulated by factors that depend on the HS 2-O sulfate modification; however, factors that contribute to MM induction are markedly sensitive to the 2-O sulfation modification. These data suggest that key defect in Hs2st null kidneys is the inability of MM to undergo induction either through a failure of mutual induction or a primary failure of MM morphogenesis. This results in normal UB formation but affects either T-shaped UB formation or iterative branching of the T-shaped UB (possibly two separate stages in collecting system development dependent upon HS). We discuss the possibility that a disruption in the interaction between HS and Wnts (e.g. Wnt 9b) may be an important aspect of the observed phenotype. This appears to be the first example of a defect in the MM preventing advancement of early UB branching past the first bifurcation stage, one of the limiting steps in early kidney development.

PMID: 20059993 http://www.ncbi.nlm.nih.gov/pubmed/20059993

A novel, low-volume method for organ culture of embryonic kidneys that allows development of cortico-medullary anatomical organization.

Sebinger DD, Unbekandt M, Ganeva VV, Ofenbauer A, Werner C, Davies JA. PLoS One. 2010 May 10;5(5):e10550.

http://www.ncbi.nlm.nih.gov/pubmed/20479933 PMID: 20479933

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010550

2009

Cell and molecular biology of kidney development

Reidy KJ, Rosenblum ND. Semin Nephrol. 2009 Jul;29(4):321-37. Review. PMID: 19615554 http://www.ncbi.nlm.nih.gov/pubmed/19615554

Semin Nephrol. 2009 Jul;29(4):321-37. Cell and molecular biology of kidney development. Reidy KJ, Rosenblum ND.

Department of Pediatrics/Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, 3415 Bainbridge Ave, Bronx, NY 10467, USA. Abstract Abnormalities of kidney and urinary tract development are the most common cause of end-stage kidney failure in childhood in the United States. Over the past 20 years, the advent of mutant and transgenic mice and the manipulation of gene expression in other animal models has resulted in major advances in identification of the cellular and molecular mechanisms that direct kidney morphogenesis, providing insights into the pathophysiology of renal and urologic anomalies. This review focuses on the molecular mechanisms that define kidney progenitor cell populations, induce nephron formation within the metanephric mesenchyme, initiate and organize ureteric bud branching, and participate in terminal differentiation of the nephron. Highlighted are common signaling pathways that function at multiple stages during kidney development, including signaling via Wnts, bone morphogenic proteins, fibroblast growth factor, sonic hedgehog, RET/glial cell-derived neurotrophic factor, and notch pathways. Also emphasized are the roles of transcription factors Odd1, Eya1, Pax2, Lim1, and WT-1 in directing renal development. Areas requiring future investigation include the factors that modulate signaling pathways to provide temporal and site-specific effects. The evolution of our understanding of the cellular and molecular mechanisms of kidney development may provide methods for improved diagnosis of renal anomalies and, hopefully, targets for intervention for this common cause of childhood end-stage kidney disease.

PMID: 19615554

How does the ureteric bud branch?

J Am Soc Nephrol. 2009 Jul;20(7):1465-9. Epub 2008 Dec 3.

Nigam SK, Shah MM.

Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA. snigam@ucsd.edu Abstract 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.

PMID: 19056872

Bladder

Endodermal origin of bladder trigone inferred from mesenchymal-epithelial interaction

J Urol. 2010 Jan;183(1):386-91.

Tanaka ST, Ishii K, Demarco RT, Pope JC 4th, Brock JW 3rd, Hayward SW.

Department of Urologic Surgery, Monroe Carell, Jr Children's Hospital at Vanderbilt, Nashville, Tennessee 37232-9820, USA. stacy.tanaka@vanderbilt.edu

Abstract PURPOSE: In the classic view of bladder development the trigone originates from the mesoderm derived wolffian ducts while the remainder of the bladder originates from the endoderm derived urogenital sinus. Recent molecular developmental studies have questioned the veracity of this received wisdom, suggesting an endodermal origin for the trigone. To shed further light on this issue we observed mesenchymal-epithelial interactions between trigone epithelium and fetal urogenital sinus mesenchyma to infer the trigonal germ layer of origin.

MATERIALS AND METHODS: Mouse trigone epithelium was recombined with fetal rat urogenital sinus mesenchyma in tissue recombinant grafts that were placed beneath the renal capsule of athymic mouse hosts. Grafts were harvested at 4 weeks. Control grafts with bladder dome and ureteral epithelium were also examined. Tissues were evaluated with hematoxylin and eosin, and Hoechst dye 33258 to confirm cell species origin. Immunohistochemistry was done with androgen receptor, broad spectrum uroplakin, dorsolateral prostate secretions and seminal vesicle secretions to differentiate prostatic and seminal vesicle differentiation.

RESULTS: Grafts of mouse trigone epithelium with fetal rat urogenital sinus mesenchyma yielded epithelial tissue that stained for dorsolateral prostate secretions but not for seminal vesicle secretions. Control grafts of bladder dome epithelium yielded the expected endodermal prostate differentiation. Control grafts of ureteral epithelium yielded the expected mesodermal seminal vesicle differentiation.

CONCLUSIONS: The consistent finding of prostatic epithelium in tissue recombinants of trigone epithelium and fetal urogenital sinus mesenchyma reinforces the hypothesis that the trigone is derived from the endoderm and not from the mesoderm, as commonly accepted.

PMID: 19914648 http://www.ncbi.nlm.nih.gov/pubmed/19914648

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794964

http://www.jurology.com/article/S0022-5347(09)02320-9/abstract