Notch signaling is a novel regulator of visceral smooth muscle cell differentiation in the murine ureter.

The contractile phenotype of smooth muscle cells (SMCs) is transcriptionally controlled by a complex of the DNA-binding protein SRF and the transcriptional co-activator MYOCD. The pathways that activate expression of Myocd and of SMC structural genes in mesenchymal progenitors are diverse, reflecting different intrinsic and extrinsic signaling inputs. Taking the ureter as a model, we analyzed whether Notch signaling, a pathway previously implicated in vascular SMC development, also affects visceral SMC differentiation. We show that mice with a conditional deletion of the unique Notch mediator RBPJ in the undifferentiated ureteric mesenchyme exhibit altered ureter peristalsis with a delayed onset, and decreased contraction frequency and intensity at fetal stages. They also develop hydroureter 2 weeks after birth. Notch signaling is required for precise temporal activation of Myocd expression and, independently, for expression of a group of late SMC structural genes. Based on additional expression analyses, we suggest that a mesenchymal JAG1-NOTCH2/NOTCH3 module regulates visceral SMC differentiation in the ureter in a biphasic and bimodal manner, and that its molecular function differs from that in the vascular system.

Connecting tubules develop from the tip of the ureteric bud in the human kidney.

The connecting tubule (CNT) is a unique segment of the nephron connecting the metanephric mesenchyme (MM)-derived distal convoluted tubule (DCT) and ureteric bud (UB)-derived collecting duct (CD). Views on the cellular origin of the CNT in the human kidney are controversial. It was suggested that in mice, the connecting segment arises from the distal compartment of the renal vesicle (RV). However, there are several differences in embryonic development between the mouse and human kidney. The aim of our study was to establish the possible origin of the CNT in the human kidney. We analysed the expression of markers defining distinct cells of the CNT CD in foetal and adult human kidneys by immunohistochemistry. Based on microscopic observation, we suggest that CNT differentiates from the outgrowth of cells of the UB tip, and therefore the CNT is an integral part of the CD system. In the adult kidney, the CNT and CD consist of functionally and morphologically similar cells expressing α- and ß-intercalated cell (IC) and principal cell (PC) markers, indicating their common origin.

Mdm4 controls ureteric bud branching via regulation of p53 activity.

The antagonism between Mdm2 and its close homolog Mdm4 (also known as MdmX) and p53 is vital for embryogenesis and organogenesis. Previously, we demonstrated that targeted disruption of Mdm2 in the Hoxb7+ ureteric bud (Ub) lineage, which gives rise to the renal collecting system, causes renal hypodysplasia culminating in perinatal lethality. In this study, we examine the unique role of Mdm4 in establishing the collecting duct system of the murine kidney. Hoxb7Cre driven loss of Mdm4 in the Ub lineage (UbMdm4-/-) disrupts branching morphogenesis and triggers UB cell apoptosis. UbMdm4-/- kidneys exhibit abnormally dilated Ub tips while the medulla is hypoplastic. These structural alterations result in secondary depletion of nephron progenitors and nascent nephrons. As a result, newborn UbMdm4-/- mice have hypo-dysplastic kidneys. Transcriptional profiling revealed downregulation of the Ret-tyrosine kinase pathway components, Gdnf, Wnt11, Sox8, Etv4 and Cxcr4 in the UbMdm4-/- mice relative to controls. Moreover, the expression levels of the canonical Wnt signaling members Axin2 and Wnt9b are downregulated. Mdm4 deletion upregulated p53 activity and p53-target gene expression including Cdkn1a (p21), Gdf15, Ccng1, PERP, and Fas. Germline loss of p53 in UbMdm4-/- mice largely rescues kidney development and terminal differentiation of the collecting duct. We conclude that Mdm4 plays a unique and vital role in Ub branching morphogenesis and collecting system development.

Proteomic analysis identifies transcriptional cofactors and homeobox transcription factors as TBX18 binding proteins.

The TBX18 transcription factor is a crucial developmental regulator of several organ systems in mice, and loss of its transcriptional repression activity causes dilative nephropathies in humans. The molecular complexes with which TBX18 regulates transcription are poorly understood prompting us to use an unbiased proteomic approach to search for protein interaction partners. Using overexpressed dual tagged TBX18 as bait, we identified by tandem purification and subsequent LC-MS analysis TBX18 binding proteins in 293 cells. Clustering of functional annotations of the identified proteins revealed a highly significant enrichment of transcriptional cofactors and homeobox transcription factors. Using nuclear recruitment assays as well as GST pull-downs, we validated CBFB, GAR1, IKZF2, NCOA5, SBNO2 and CHD7 binding to the T-box of TBX18 in vitro. From these transcriptional cofactors, CBFB, CHD7 and IKZF2 enhanced the transcriptional repression of TBX18, while NCOA5 and SBNO2 dose-dependently relieved it. All tested homeobox transcription factors interacted with the T-box of TBX18 in pull-down assays, with members of the Pbx and Prrx subfamilies showing coexpression with Tbx18 in the developing ureter of the mouse. In summary, we identified and characterized new TBX18 binding partners that may influence the transcriptional activity of TBX18 in vivo.

Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development.

Eukaryotic cilia are assembled by intraflagellar transport (IFT) where large protein complexes called IFT particles move ciliary components from the cell body to the cilium. Defects in most IFT particle proteins disrupt ciliary assembly and cause mid gestational lethality in the mouse. IFT25 and IFT27 are unusual components of IFT-B in that they are not required for ciliary assembly and mutant mice survive to term. The mutants die shortly after birth with numerous organ defects including duplex kidneys. Completely duplex kidneys result from defects in ureteric bud formation at the earliest steps of metanephric kidney development. Ureteric bud initiation is a highly regulated process involving reciprocal signaling between the ureteric epithelium and the overlying metanephric mesenchyme with regulation by the peri-Wolffian duct stroma. The finding of duplex kidney in Ift25 and Ift27 mutants suggests functions for these genes in regulation of ureteric bud initiation. Typically the deletion of IFT genes in the kidney causes rapid cyst growth in the early postnatal period. In contrast, the loss of Ift25 results in smaller kidneys, which show only mild tubule dilations that become apparent in adulthood. The smaller kidneys appear to result from reduced branching in the developing metanephric kidney. This work indicates that IFT25 and IFT27 are important players in the early development of the kidney and suggest that duplex kidney is part of the ciliopathy spectrum.

Protein Kinase 2ß Is Expressed in Neural Crest-Derived Urinary Pacemaker Cells and Required for Pyeloureteric Contraction.

Nonobstructive hydronephrosis, defined as dilatation of the renal pelvis with or without dilatation of the ureter, is the most common antenatal abnormality detected by fetal ultrasound. Yet, the etiology of nonobstructive hydronephrosis is poorly defined. We previously demonstrated that defective development of urinary tract pacemaker cells (utPMCs) expressing hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) and the stem cell marker cKIT causes abnormal ureteric peristalsis and nonobstructive hydronephrosis. However, further investigation of utPMC development and function is limited by lack of knowledge regarding the embryonic derivation, development, and molecular apparatus of these cells. Here, we used lineage tracing in mice to identify cells that give rise to utPMCs. Neural crest cells (NCCs) indelibly labeled with tdTomato expressed HCN3 and cKIT. Furthermore, purified HCN3+ and cKIT+ utPMCs were enriched in Sox10 and Tfap-2α, markers of NCCs. Sequencing of purified RNA from HCN3+ cells revealed enrichment of a small subset of RNAs, including RNA encoding protein kinase 2ß (PTK2ß), a Ca2+-dependent tyrosine kinase that regulates ion channel activity in neurons. Immunofluorescence analysis in situ revealed PTK2ß expression in NCCs as early as embryonic day 12.5 and in HCN3+ and cKIT+ utPMCs as early as embryonic day 15.5, with sustained expression in HCN3+ utPMCs until postnatal week 8. Pharmacologic inhibition of PTK2ß in murine pyeloureteral tissue explants inhibited contraction frequency. Together, these results demonstrate that utPMCs are derived from NCCs, identify new markers of utPMCs, and demonstrate a functional contribution of PTK2ß to utPMC function.

Generation of branching ureteric bud tissues from human pluripotent stem cells.

Recent progress in kidney regeneration research is noteworthy. However, the selective and robust differentiation of the ureteric bud (UB), an embryonic renal progenitor, from human pluripotent stem cells (hPSCs) remains to be established. The present study aimed to establish a robust induction method for branching UB tissue from hPSCs towards the creation of renal disease models. Here, we found that anterior intermediate mesoderm (IM) differentiates from anterior primitive streak, which allowed us to successfully develop an efficient two-dimensional differentiation method of hPSCs into Wolffian duct (WD) cells. We also established a simplified procedure to generate three-dimensional WD epithelial structures that can form branching UB tissues. This system may contribute to hPSC-based regenerative therapies and disease models for intractable disorders arising in the kidney and lower urinary tract.

Asymmetric BMP4 signalling improves the realism of kidney organoids.

We present a strategy for increasing the anatomical realism of organoids by applying asymmetric cues to mimic spatial information that is present in natural embryonic development, and demonstrate it using mouse kidney organoids. Existing methods for making kidney organoids in mice yield developing nephrons arranged around a symmetrical collecting duct tree that has no ureter. We use transplant experiments to demonstrate plasticity in the fate choice between collecting duct and ureter, and show that an environment rich in BMP4 promotes differentiation of early collecting ducts into uroplakin-positive, unbranched, ureter-like epithelial tubules. Further, we show that application of BMP4-releasing beads in one place in an organoid can break the symmetry of the system, causing a nearby collecting duct to develop into a uroplakin-positive, broad, unbranched, ureter-like 'trunk' from one end of which true collecting duct branches radiate and induce nephron development in an arrangement similar to natural kidneys. The idea of using local symmetry-breaking cues to improve the realism of organoids may have applications to organoid systems other than the kidney.

The developmental programme for genesis of the entire kidney is recapitulated in Wilms tumour.

Wilms tumour (WT) is an embryonal tumour that recapitulates kidney development. The normal kidney is formed from two distinct embryological origins: the metanephric mesenchyme (MM) and the ureteric bud (UB). It is generally accepted that WT arises from precursor cells in the MM; however whether UB-equivalent structures participate in tumorigenesis is uncertain. To address the question of the involvement of UB, we assessed 55 Wilms tumours for the molecular features of MM and UB using gene expression profiling, immunohistochemsitry and immunofluorescence. Expression profiling primarily based on the Genitourinary Molecular Anatomy Project data identified molecular signatures of the UB and collecting duct as well as those of the proximal and distal tubules in the triphasic histology group. We performed immunolabeling for fetal kidneys and WTs. We focused on a central epithelial blastema pattern which is the characteristic of triphasic histology characterized by UB-like epithelial structures surrounded by MM and MM-derived epithelial structures, evoking the induction/aggregation phase of the developing kidney. The UB-like epithelial structures and surrounding MM and epithelial structures resembling early glomerular epithelium, proximal and distal tubules showed similar expression patterns to those of the developing kidney. These observations indicate WTs can arise from a precursor cell capable of generating the entire kidney, such as the cells of the intermediate mesoderm from which both the MM and UB are derived. Moreover, this provides an explanation for the variable histological features of mesenchymal to epithelial differentiation seen in WT.

[PATHOGENICALLY INDUCED APOPTOSIS CAUSED BY HYPOXIC EFFECTS IN THE URINARY SYSTEM ORGANS OF FETUSES AND NEWBORNS (EXPERIMENTAL STUDY)].

The purpose of the study was to identify the characteristics of apoptosis in the kidneys, ureters and bladder of fetuses and newborns in the modeling of chronic intrauterine hypoxia, acute postnatal hypoxia and mixed hypoxia. An experiment was conducted on WAG rats for modeling high altitude hypoxia. Experimental animals were divided into four groups: I - control - fetuses and newborns from healthy rats; II - modeling of chronic intrauterine hypoxia; III - modeling of acute postnatal hypoxia; IV - modeling of mixed hypoxia. The material of the study was the tissue of the kidneys, ureters and bladder of fetuses and newborns. In group I in the kidneys of fetuses the mean value of the number of p53-positive cells was 7.83±0.31, newborns - 5.40±0.28; in the ureters and bladder of fetuses - 5.77±0.29 and 6.97±0.32, newborns - 3.58±0.21 and 5.36±0.28. In the kidneys in group II the mean value of the number of p53-expressing cells in fetuses was 1.43±0.50, in newborns - 21.72±0.58; in group III in newborns - 15.03±0.63; in group IV in newborns - 33.33±0.72. The mean value of the number of p53-expressing cells in the ureters and bladder in group II in fetuses was 13.17±0.49 and 11.83±0.43, in newborns - 16.24±0.37 and 15.38±0.37; in group III in newborns - 7.25±0.27 and 8.68±0.32; in group IV in newborns - 19.63±0.31and 21.03±0.40. As the result of the study it was found that experimental hypoxia induced apoptotic processes in the kidneys, ureters and bladder of fetuses and newborns, the severity of which was moderate in the modeling of acute postnatal hypoxia, expressed in the modeling of chronic intrauterine hypoxia and strongly expressed in the modeling of mixed hypoxia. Under the influence of acute postnatal hypoxia, chronic intrauterine hypoxia and mixed hypoxia in the ureters and bladder of fetuses and newborns p53-positive cells were located evenly in all layers of the wall of these organs, whereas in the kidneys p53-positive cells prevailed in the tubular component. In the modeling of chronic intrauterine hypoxia apoptotic processes in the kidneys, ureters and bladder increased in newborns in comparison with fetuses.

Hydronephrosis in the Wnt5a-ablated kidney is caused by an abnormal ureter-bladder connection.

The Wnt5a null mouse is a complex developmental model which, among its several posterior-localized axis defects, exhibits multiple kidney phenotypes, including duplex kidney and loss of the medullary zone. We previously reported that ablation of Wnt5a in nascent mesoderm causes duplex kidney formation as a result of aberrant development of the nephric duct and abnormal extension of intermediate mesoderm. However, these mice also display a loss of the medullary region late in gestation. We have now genetically isolated duplex kidney formation from the medullary defect by specifically targeting the progenitors for both the ureteric bud and metanephric mesenchyme. The conditional mutants fail to form a normal renal medulla but no longer exhibit duplex kidney formation. Approximately 1/3 of the mutants develop hydronephrosis in the kidneys either uni- or bilaterally when using Dll1Cre. The abnormal kidney phenotype becomes prominent at E16.5, which approximates the time when urine production begins in the mouse embryonic kidney, and is associated with a dramatic increase in apoptosis only in mutant kidneys with hydronephrosis. Methylene blue dye injection and histologic examination reveal that aberrant cell death likely results from urine toxicity due to an abnormal ureter-bladder connection. This study shows that Wnt5a is not required for development of the renal medulla and that loss of the renal medullary region in the Wnt5a-deleted kidney is caused by an abnormal ureter-bladder connection.

Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate.

The T-box transcription factor TBX18 is essential to mesenchymal cell differentiation in several tissues and Tbx18 loss-of-function results in dramatic organ malformations and perinatal lethality. Here we demonstrate for the first time that Tbx18 is required for the normal development of periductal smooth muscle stromal cells in prostate, particularly in the anterior lobe, with a clear impact on prostate health in adult mice. Prostate abnormalities are only subtly apparent in Tbx18 mutants at birth; to examine postnatal prostate development we utilized a relatively long-lived hypomorphic mutant and a novel conditional Tbx18 allele. Similar to the ureter, cells that fail to express Tbx18 do not condense normally into smooth muscle cells of the periductal prostatic stroma. However, in contrast to ureter, the periductal stromal cells in mutant prostate assume a hypertrophic, myofibroblastic state and the adjacent epithelium becomes grossly disorganized. To identify molecular events preceding the onset of this pathology, we compared gene expression in the urogenital sinus (UGS), from which the prostate develops, in Tbx18-null and wild type littermates at two embryonic stages. Genes that regulate cell proliferation, smooth muscle differentiation, prostate epithelium development, and inflammatory response were significantly dysregulated in the mutant urogenital sinus around the time that Tbx18 is first expressed in the wild type UGS, suggesting a direct role in regulating those genes. Together, these results argue that Tbx18 is essential to the differentiation and maintenance of the prostate periurethral mesenchyme and that it indirectly regulates epithelial differentiation through control of stromal-epithelial signaling.

Fibroblast growth factor receptor signaling in kidney and lower urinary tract development.

Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development. FGFR signaling has been shown to be critical for early metanephric mesenchymal patterning, Wolffian duct patterning including induction of the ureteric bud, ureteric bud branching morphogenesis, nephron progenitor survival and nephrogenesis, and bladder mesenchyme patterning. FGFRs pattern these tissues by interacting with many other growth factor signaling pathways. Moreover, the many genetic Fgfr and Fgf animal models have structural defects mimicking numerous congenital anomalies of the kidney and urinary tract seen in humans. Finally, many studies have shown how FGFR signaling is critical for kidney and lower urinary tract patterning in humans.

A morphological investigation of sexual and lateral dimorphism in the developing metanephric kidney.

Sexual dimorphism is a prominent feature of renal physiology and as a consequence, it differentially affects predisposition to many adult kidney diseases. Furthermore the left and right kidneys differ in terms of their position, size and involvement in congenital malformations of the urogenital tract. We set out to determine whether differences in the program of branching morphogenesis that establishes the basic architecture of the kidney were apparent with respect to either sex or laterality in mouse embryonic kidneys. This was achieved using a combination of optical projection tomography imaging and computational analysis of many spatial metrics describing the branched ureteric tree. We undertook a comprehensive assessment of twelve aspects of ureteric morphology across developmental time and we found no consistent differences between kidneys of different sexes or laterality. These results suggest that dimorphism is established after birth or at a physiological or cellular level that is not reflected in the morphology of the ureteric tree.

Comparing and distinguishing the structure of biological branching.

Bifurcating developmental branching morphogenesis gives rise to complex organs such as the lung and the ureteric tree of the kidney. However, a few quantitative methods or tools exist to compare and distinguish, at a structural level, the critical features of these important biological systems. Here we develop novel graph alignment techniques to quantify the structural differences of rooted bifurcating trees and demonstrate their application in the analysis of developing kidneys from in normal and mutant mice. We have developed two graph based metrics: graph discordance, which measures how well the graphs representing the branching structures of distinct trees graphs can be aligned or overlayed; and graph inclusion, which measures the degree of containment of a tree graph within another. To demonstrate the application of these approaches we first benchmark the discordance metric on a data set of 32 normal and 28Tgfß(+/-) mutant mouse ureteric trees. We find that the discordance metric better distinguishes control and mutant mouse kidneys than alternative metrics based on graph size and fingerprints - the distribution of tip depths. Using this metric we then show that the structure of the mutant trees follows the same pattern as the normal kidneys, but undergo a major delay in elaboration at later stages. Analysis of both controls and mutants using the inclusion metric gives strong support to the hypothesis that ureteric tree growth is stereotypic. Additionally, we present a new generalised multi-tree alignment algorithm that minimises the sum of pairwise graph discordance and which can be used to generate maximum consensus trees that represent the archetype for fixed developmental stages. These tools represent an advance in the analysis and quantification of branching patterns and will be invaluable in gaining a deeper understanding of the mechanisms that drive development. All code is being made available with documentation and example data with this publication.

Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension.

Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in 500 births and are a major cause of morbidity in infants. Duplex collecting systems rank among the most common abnormalities of CAKUT, but the molecular basis for this defect is poorly understood. In mice, conditional deletion of Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The ureteric buds (UBs) in mutants emerge as doublets from the intermediate mesoderm (IM)-derived nephric duct (ND) without anterior expansion of the glial cell line-derived neurotrophic factor (Gdnf) expression domain in the surrounding mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5. Furthermore, ablation of Wnt5a in the mesoderm with an inducible Cre at E7.5 results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth, demonstrating that Wnt5a functions in IM development well before the formation of the metanephros. In mutants, the posterior ND is duplicated and surrounding Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that disruption of normal ND patterning prompts the formation of duplex ureters and kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting systems, show a dramatic increase in incidence with the additional deletion of one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling during IM development. This work provides the first evidence of a role of Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of CAKUT and possible involvement of Wnt5a/Ror2 mutations.

Stage specific requirement of Gfrα1 in the ureteric epithelium during kidney development.

Glial cell line-derived neurotrophic factor (GDNF) binds a coreceptor GDNF family receptor α1 (GFRα1) and forms a signaling complex with the receptor tyrosine kinase RET. GDNF-GFRα1-RET signaling activates cellular pathways that are required for normal induction of the ureteric bud (UB) from the Wolffian duct (WD). Failure of UB formation results in bilateral renal agenesis and perinatal lethality. Gfrα1 is expressed in both the epithelial and mesenchymal compartments of the developing kidney while Ret expression is specific to the epithelium. The biological importance of Gfrα1's wider tissue expression and its role in later kidney development are unclear. We discovered that conditional loss of Gfrα1 in the WD epithelium prior to UB branching is sufficient to cause renal agenesis. This finding indicates that Gfrα1 expressed in the nonepithelial structures cannot compensate for this loss. To determine Gfrα1's role in branching morphogenesis after UB induction we used an inducible Gfrα1-specific Cre-deletor strain and deleted Gfrα1 from the majority of UB tip cells post UB induction in vivo and in explant kidney cultures. We report that Gfrα1 excision from the epithelia compartment after UB induction caused a modest reduction in branching morphogenesis. The loss of Gfrα1 from UB-tip cells resulted in reduced cell proliferation and decreased activated ERK (pERK). Further, cells without Gfrα1 expression are able to populate the branching UB tips. These findings delineate previously unclear biological roles of Gfrα1 in the urinary tract and demonstrate its cell-type and stage-specific requirements in kidney development.

Brg1 determines urothelial cell fate during ureter development.

Developing and adult ureters express the epigenetic regulator Brg1, but the role of Brg1 in ureter development is not well understood. We conditionally ablated Brg1 in the developing ureter using Hoxb7-Cre and found that Brg1 expression is upstream of p63, Pparγ, and sonic hedgehog (Shh) expression in the ureteral epithelium. In addition, epithelial stratification in the basal cells required Brg1-dependent p63 expression, whereas terminal differentiation of the umbrella cells required Brg1-dependent Pparγ expression. Furthermore, the loss of ureteric Brg1 resulted in failure of Shh expression, which correlated with reduced smooth muscle cell development and hydroureter. Taken together, we conclude that Brg1 expression unifies three aspects of ureter development: maintenance of the basal cell population, guidance for terminal differentiation of urothelial cells, and proper investment of ureteral smooth muscle cells.

Lower urinary tract development and disease.

Congenital anomalies of the lower urinary tract (CALUT) are a family of birth defects of the ureter, the bladder, and the urethra. CALUT includes ureteral anomaliesc such as congenital abnormalities of the ureteropelvic junction (UPJ) and ureterovesical junction (UVJ), and birth defects of the bladder and the urethra such as bladder-exstrophy-epispadias complex (BEEC), prune belly syndrome (PBS), and posterior urethral valves (PUVs). CALUT is one of the most common birth defects and is often associated with antenatal hydronephrosis, vesicoureteral reflux (VUR), urinary tract obstruction, urinary tract infections (UTI), chronic kidney disease, and renal failure in children. Here, we discuss the current genetic and molecular knowledge about lower urinary tract development and genetic basis of CALUT in both human and mouse models. We provide an overview of the developmental processes leading to the formation of the ureter, the bladder, and the urethra, and different genes and signaling pathways controlling these developmental processes. Human genetic disorders that affect the ureter, the bladder and the urethra and associated gene mutations are also presented. As we are entering the postgenomic era of personalized medicine, information in this article may provide useful interpretation for the genetic and genomic test results collected from patients with lower urinary tract birth defects. With evidence-based interpretations, clinicians may provide more effective personalized therapies to patients and genetic counseling for their families.

Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system.

The mammalian kidney, which at maturity contains thousands of nephrons joined to a highly branched collecting duct (CD) system, is an important model system for studying the development of a complex organ. Furthermore, congenital anomalies of the kidney and urinary tract, often resulting from defects in ureteric bud branching morphogenesis, are relatively common human birth defects. Kidney development is initiated by interactions between the nephric duct and the metanephric mesenchyme, leading to the outgrowth and repeated branching of the ureteric bud epithelium, which gives rise to the entire renal CD system. Meanwhile, signals from the ureteric bud induce the mesenchyme cells to form the nephron epithelia. This review focuses on development of the CD system, with emphasis on the mouse as an experimental system. The major topics covered include the origin and development of the nephric duct, formation of the ureteric bud, branching morphogenesis of the ureteric bud, and elongation of the CDs. The signals, receptors, transcription factors, and other regulatory molecules implicated in these processes are discussed. In addition, our current knowledge of cellular behaviors that are controlled by these genes and underlie development of the collecting system is reviewed.