Search

Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor for embryonic midbrain dopaminergic, spinal motor, cranial sensory, sympathetic, and hindbrain noradrenergic neurons, and is available to these cells in vivo. It is therefore considered a physiological trophic factor and a potential therapeutic agent for Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here we show that at postnatal day 0 (P0), GDNF-deficient mice have deficits in dorsal root ganglion, sympathetic and nodose neurons, but not in hindbrain noradrenergic or midbrain dopaminergic neurons. These mice completely lack the enteric nervous system (ENS), ureters and kidneys. Thus GDNF is important for the development and/or survival of enteric, sympathetic and sensory neurons and the renal system, but is not essential for catecholaminergic neurons in the central nervous system (CNS).

Nephrons develop from mesenchymal cells that have contacted the ureteric bud (UB). To determine whether cell associated or secreted ureteric molecules induce the mesenchyme, we have isolated UB cell lines from mice transgenic for T antigen. These cells express epithelial and ureteric (Dolichos lectin staining, c-ret, c-met without hepatocyte growth factor) specific markers, which identifies them as authentic UB cells. Medium conditioned by our cells rescues mesenchyme from apoptosis without inducing the appearance of epithelial aggregates. The same was found by culturing mesenchymes upon the apical surface of a UB monolayer. In contrast, tubules were induced in mesenchymes contacting trypsinized pellets of UB cells. As revealed by staining for T antigen and Dolichos lectin or by prelabeling UB cells with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), we found that our cells encapsulated the mesenchyme but did not incorporate in the tubules. These data demonstrate that nephrogenesis is stimulated by two distinct ureteric signals, secreted molecules rescue the mesenchyme from apoptosis, whereas diffusion-limited basolateral molecules trigger mesenchymal/epithelial conversion.

Metanephric mesenchyme gives rise to both the epithelial cells of the nephron and the stromal cells of the mature kidney. The function of the stroma. in kidney morphogenesis is poorly understood. We have generated mice with a null mutation in the Winged Helix (WH) transcription factor BF-2 to examine its function during development. BF-2 expression within the developing kidney is restricted to the stromal cell lineage. Homozygotes die within the first 24 hr after birth with abnormal kidneys. Mutant kidneys are small, fused longitudinally, and rotated 90 degrees ventrally. Histological examination reveals a smaller collecting system, numerous large condensations of mesenchyme, and a decrease in the number of nephrons. Using molecular markers we show that induction and condensation of the nephrogenic mesenchyme occurs normally in mutant. The disruption of BF-2 reduces the rate of differentiation of the condensed mesenchyme into tubular epithelium, as well as the rate of growth and branching of the ureter and collecting system. Our findings demonstrate that BF-2 and stromal cells have essential functions during kidney morphogenesis. Furthermore, they suggest that BF-2 controls the production, by the stroma, of signals or factors that are required for the normal transition of induced mesenchyme into tubular epithelium and full growth and branching of the collecting system.

The c-ret gene encodes a receptor tyrosine kinase that is expressed in the Wolffian duct and ureteric bud of the developing excretory system. Newborn mice homozygous for a mutation in c-ret displayed renal agenesis or severe hypodysplasia, suggesting a critical role for this gene in metanephric kidney development. To investigate the embryological basis of these defects, we characterized the early development of the excretory system in mutant homozygotes, and observed a range of defects in the formation, growth and branching of the ureteric bud, which account for the spectrum of renal defects seen at birth. Co-culture of isolated ureteric buds and metanephric mesenchyme show that the primary defect is intrinsic to the ureteric bud. While the mutant bud failed to respond to induction by wild-type mesenchyme, mutant mesenchyme was competent to induce the growth and branching of the wild-type bud. Furthermore, the mutant metanephric mesenchyme displayed a normal capacity to differentiate into nephric tubules when co-cultured with embryonic spinal cord. These findings suggest a model in which c-ret encodes the receptor for a (yet to be identified) factor produced by the metanephric mesenchyme, which mediates the inductive effects of this tissue upon the ureteric bud. This factor appears to stimulate the initial evagination of the ureteric bud from the Wolffian duct, as well as its subsequent growth and branching.

Vitamin A and its metabolic derivatives are known to be key signalling molecules in regulating morphogenetic events in vertebrate development. Here we investigated their possible involvement during mammalian kidney development using paired rat metanephros organ culture. Metanephroi were explanted from 14-day-old embryos and cultured for six days in a chemically defined medium containing a retinoid at a dose of 10(-11) to 10(-4) M. Retinol, all-trans and 9-cis retinoic acid were able to promote metanephros growth and differentiation in vitro. A significant increase in the number of nephrons was observed from 10(-8) M of retinol and 10(-10) M of all-trans retinoic acid, before any change in growth parameters. A threefold increase in the number of nephrons was obtained at a dose of 10(-6) M. At low retinoid concentrations, there was a modulating effect of triiodothyronine on retinoid-stimulated nephrogenesis since the absence of triiodothyronine in the medium enhanced the nephrogenic stimulation. Exposure of metanephroi from 13-day-old embryos to all-trans retinoic acid (10(-7) M) led to a sixfold increase of nephron formation. Finally, we analyzed the branching pattern of the ureteric bud and showed that within 48 hours of culture, it was significantly more developed upon retinoid exposure. In conclusion, this study demonstrates that retinoic acid is a key regulator of renal organogenesis in controlling nephrogenic induction processes and ureteric bud patterning, and that the younger the metanephros, the greater the effect.

Transgenic mice expressing wild-type murine p53 under the control of the mouse mammary tumor virus long terminal repeat (MMTV LTR) undergo progressive renal failure due to abnormal kidney development. Similar phenotypes are observed in two transgenic lines that express wild-type p53 within the ureteric bud but not in transgenic animals expressing a dominant-negative p53 mutant allele. Defective differentiation of the ureteric bud, as evidenced by altered marker expression during development, accompanies expression of the p53 transgene. At E17.5-18.5, metanephric mesenchymal cells undergo high rates of apoptosis, and fewer cells than normal are converted to tubular epithelium. As a result, p53 transgenic kidneys grow to only half of their expected size and contain about half of the normal number of nephrons, with compensatory hypertrophy of the glomeruli. In this setting, rather than arrest the cell cycle or induce apoptosis directly, abnormally high levels of wild-type p53 appear to alter cellular differentiation in embryonic ureteric buds and cause secondary effects (apoptosis and inefficient conversion to epithelium) in the adjacent undifferentiated mesenchyme.

Background: Control of testicular descent is poorly understood. There are a number of mammalian species in which testis descent does not occur, and the phenomenon is called testicondia. Analysis of foetal development of such species could contribute to a better understanding of the key events in anatomical development underlying testis descent. Specific attention is to be given to the development of the so-called gubernaculum of Hunter: a structure of complex architecture and composition, which extends from the caudal pole of the mesonephric remnants into the inguinal abdominal wall and which is present in most mammals but not in submammalian vertebrates., Methods: Serially sectioned male and female foetuses of Hyrax capensis, a species in which testes remain close to the caudal pole of the kidneys throughout life, were analysed for architecture of the developing genital apparatus and the immediately surrounding structures. The results of this analysis were compared with those from a similar analysis of reptiles, of monotremata without testis descent, and of mammals with testis descent., Results: Reptiles and Monotremata showed no gubernacular structures. Mammals with testis descent showed gubernacular growth and differentiation which varied between the sexes and with the stage of foetal development. Hyrax capensis foetuses showed the development of only one component of the gubernaculum: the gubernacular cord as a part of the mesonephric mesentery and extending between the caudal pole of the mesonephros (or mesonephric remnants in older foetuses) and the lateral bladder ligament. No part developed in the inguinal abdominal wall components, which are the primordia of the cremaster sacs in species with testis descent., Conclusion: Hyrax capensis shows only partial development of the gubernacular structures, and, specifically, the primordia of the cremaster sacs remain absent. Thus, this species lacks a key anatomical condition for testis descent. Gubernacular architecture in Hyrax capensis seems of a degree intermediate between egg laying monotremata mammals and mammals with testis descent. A model is proposed within which to understand the development of the gubernacular components within the mammalian class.

Hydronephrosis caused by pelvi-ureteric junction obstruction (PUJO) is a frequent urological malformation assumed to result from a deficient development of the ureteric bud. The exact etiology of pelvi-ureteric junction stenosis is unknown, but there is convincing evidence for a genetic cause, with linkage analysis predicting a hereditary hydronephrosis locus on chromosome 6p. We encountered a patient with a de novo autosomal t(6;19)(p21;q13.1) and attendant bilateral multicystic renal dysplasia (MRD), bilateral PUJO resulting in massive hydronephrosis, and an associated von Mayer-Rokitansky-Kuster disorder. On the basis of the presumption that in this patient the putative hydronephrosis gene might be disrupted by the translocation, we sought to isolate DNA from the breakpoint regions as the initial step in a strategy to identify genes affected by the t(6; 19). Using sequential rounds of fluorescence in situ hybridization (FISH) with cosmids selected from a detailed integrated map of the long arm of chromosome 19, we have identified a cosmid clone that spans the breakpoint. The position of the breakpoint was further localized by Southern blot analysis. Using a vectorette PCR approach, rearranged DNA fragments were isolated and, by comparative nucleotide sequence analysis, these were shown to contain ectopic sequences. A cosmid clone containing these ectopic sequences was isolated and shown by CASH (chromosome assignment using somatic cell hybrids) and FISH (fluorescence in situ hybridization) analysis to map to the short arm of chromosome 6 and to span the breakpoint found in the MRD patient. The isolated cosmid clones are useful reagents for analysis of other MRD patients and for the search for genes at or flanking the breakpoints.

Objective: To determine the spatial and temporal distribution of nitric oxide synthase (NOS) in the urogenital organs of a series of human male fetuses, using an immunohistochemical technique., Material and Methods: Thirteen pre-natal specimens ranging in gestational age from 13 to 30 weeks were acquired following abortion or miscarriage. The distribution of NOS, which catalyses the production of nitric oxide (NO), was revealed using an indirect immunolabelling technique and compared with the overall innervation of each specimen visualized using the general nerve-marker protein gene product 9.5 (PGP)., Results: At 13 weeks of gestation the majority of nerves supplying the developing prostate gland expressed NOS while similar nerves formed a very minor proportion of the total innervation to the urinary bladder and intramural ureters. With increasing gestational age, NOS-containing nerves became more numerous in the lower urinary tract, the majority occurring at the bladder neck and around the prostatic urethra. In contrast, NOS-containing nerves were not detected in the muscle coat of the vas deferens and seminal vesicle until 23 weeks of gestation and at 30 weeks still only formed a small proportion of the intramuscular nerves. From 23 weeks onwards NOS-containing nerves were present occasionally in the dense subepithelial nerve plexuses which developed in the bladder, prostate, vas deferens and seminal vesicle. Also from 23 weeks onwards, many of the epithelial cells lining the vas deferens, seminal vesicle and ejaculatory ducts showed immunoreactivity to NOS but no immunoreactivity was observed in the epithelial lining of the urinary bladder and the intramural ureters., Conclusion: Based on the comparative density of NOS-containing nerves and the difference in their temporal development among the various urogenital organs it is apparent that NO plays an increasingly important role in the autonomic control of the lower urinary tract during fetal development but that its involvement in the functional control of the vas deferens and seminal vesicle is relatively minor before birth.

The kidney forms from two tissue populations derived from intermediate mesoderm, the ureteric bud and metanephric mesenchyme. It is currently accepted that metanephric mesenchyme is committed to differentiating into nephrons while the ureteric bud is restricted to forming the renal collecting system. To test this hypothesis, we transferred lacZ into pure metanephric mesenchyme isolated from gestation day 13 rat embryos. The fate of tagged mesenchymal cells and their progeny was characterized after co-culture with isolated ureteric buds. When induced to differentiate by the native inducer of kidney morphogenesis, lineage-tagged mesenchymal cells exhibit the potential to differentiate into collecting system epithelia, in addition to nephrons. The fate of cells deriving from isolated ureteric buds was also examined and results of these lacZ gene transfer experiments indicate that the majority of ureteric bud cells differentiate into the renal collecting system. These cell fate studies combined with in situ morphological observations raise the possibility that collecting system morphogenesis in vivo occurs by growth of the ureteric bud and recruitment of mesenchymal cells from the metanephric blastema. Thus, metanephric mesenchyme may be a pluripotent renal stem population.

Kidney epithelia have separate origins; collecting ducts develop by ureteric bud growth and arborisation, nephrons by induced mesenchyme-epithelium transition. Both express sulphated glycosaminoglycans (GAGs) which are strikingly upregulated during nephron differentiation. However, sodium chlorate, an inhibitor of GAG sulphation, and the GAG-degrading enzymes heparitinase plus chondroitinase, did not prevent nephron development. In contrast, ureteric bud growth and branching were reversibly inhibited by the above reagents, the inhibition correlating quantitatively with sulphated GAG deprivation caused by a range of chlorate concentrations. Growth and branching could be independently restored during GAG deprivation by hepatocyte growth factor and phorbol-12-myristate acetate (PMA) respectively. Together these signalling effectors stimulated both branch initiation and growth. Thus growth and morphogenesis of ureteric bud involve distinct signalling pathways both regulated by GAGs.

Histologic and Transforming Growth Factor Beta (TGF-beta) immunostain patterns were sought in resected distal urinary tracts from 17 Primary Megaureter (PM) affected children, referred to surgery. Comparative observations were also carried out on embryonal and fetal ureteral buds of both humans and bovines. A reciprocal resemblance was mainly objectivized between the resected "narrowed" ureters of patients under 18 months, and the fetal ureteral buds at 26th and 38th gestational week. A development delay was irrespectively observed in PM "narrowed" ureters, at the longitudinal muscle-bundles in the parietal juxta-luminal compartment. A consistent TGF-beta immunostain cytoplasmic reaction there selectively depicted the growing mesenchymal lines, including both the undifferentiated single cells and the muscle-like profiled ones. These results agree with very recent reports perspecting a segmental maturation delay as a pathogenetic moment of PM. Because of the acquired potent TGF-beta inhibitory role on myoblasts differentiation, the present study substantiates a persistent TGF-beta role in perinatal ureter dilations.

Uterus didelphys with double vagina and hemi-vaginal atresia is a rare syndrome of congenital anomalies. A 17-year-old girl had a right blind-ending ectopic ureter, the proximal end of which communicated with the ipsilateral uterine cervix of uterus didelphys. The patient presented with vaginal urinary incontinence after incision of the vaginal wall for right hemi-hematocolpometra. Following various examinations, the ipsilateral kidney was found to be absent. The ectopic ureter and communicating duct were resected, and the fistula was closed. The genesis of malformation of the female genitalia and urinary tract resulting in such a unique communication is discussed. The importance of preoperative meticulous examinations, including cysto-genitography, pelvic magnetic resonance imaging and panendoscopy with the patient under anesthesia, is emphasized.

We report a case of an ectopic ureter opening into a distorted cystic seminal vesicle, with ipsilateral renal aplasia and an unusual presentation. Literature relevant to its embryology and management is discussed.

A rare case of multiple urological anomalies is presented. The chief complaint of the patient, a 12-year-old girl, was urinary incontinence. Radiologic and endoscopic examinations revealed that the patient had a normal left kidney and ureter, a left ectopic blind-ending ureter that opened near the neck of the bladder, and right complete double ureters with an ectopic orifice that opened on the left of the external urethral meatus. This orifice was responsible for her urinary incontinence. Right ureteroneocystostomy was performed and the incontinence was cured. An attempt was made to explain the embryological origin of the anomalies observed in this case. We postulated that during development, on the left, there were three ureteral buds on the mesonephric duct. The first bud was at the normal position and drained the left kidney in a normal manner. The second bud was cranial from the normal position on the mesonephric duct and was associated with growth in an abnormal direction. This bud made contact with the upper portion of the right metanephric mass. The last bud grew between the two aforementioned buds. This bud was not draped by the metanephric mass and became the blind-ending ureter. On the right, one ureteral bud was located on the mesonephric duct and it made contact with a metanephric mass that became the right kidney. The upper part of the right kidney was drained by the ureter that had originally been located on the left mesonephric duct. This condition should be termed crossed ureteral ectopia rather than crossed renal ectopia, since the ureter was the structure that crossed.

The kidney has been widely exploited as a model system for the study of tissue inductions regulating vertebrate organogenesis. Kidney development is initiated by the ingrowth of the Wolfian duct-derived ureteric bud into the presumptive kidney mesenchyme. In response to a signal from the ureter, mesenchymal cells condense, aggregate into pretubular clusters and undergo an epithelial conversion generating a simple tubule. This then undergoes morphogenesis and is transformed into the excretory system of the kidney, the nephron. We report here that the expression of Wnt-4, which encodes a secreted glycoprotein, correlates with, and is required for, kidney tubulogenesis. Mice lacking Wnt-4 activity fail to form pretubular cell aggregates; however, other aspects of mesenchymal and ureteric development are unaffected. Thus, Wnt-4 appears to act as an autoinducer of the mesenchyme to epithelial transition that underlies nephron development.

Mice which are homozygous for the limb deformity (ld) mutation also manifest an incompletely penetrant unilateral or bilateral renal agenesis phenotype. Intercross experiments suggest that the differences in penetrance of the renal agenesis phenotype between homozygous mice with different ld alleles are due to intrinsic differences in the strength of the mutant alleles or to one or more closely linked modifying loci, and not to generalized differences in genetic background. Analysis of ld/ld embryos between embryonic days 11-13 reveals delayed outgrowth or complete absence of the ureteric bud, the inducer of metanephric mesenchyme. Since explants of ld/ld metanephric mesenchyme differentiate in culture when apposed to embryonic spinal cord, we conclude that deficient ureteric bud outgrowth is the morphologic basis for renal agenesis in ld/ld mice. However, since ld transcripts can be detected in both metanephric mesenchyme and ureteric bud, the molecular basis for the deficiency in ureteric bud outgrowth could reside in either component.

Epithelial glomerular cells differentiate from mesenchymal cells of the metanephrogenic blastema. During the first stages of glomerulogenesis, the cells acquire the morphological features of epithelial cells. Then, podocytes lose these characteristics at the maturing glomerular stage. We have studied the molecules associated with junctional complexes during glomerular differentiation in human and pig fetal kidneys. We show for the first time the expression of P-cadherin in renal cells. Epithelial cells of ureteral buds and ampullae display all the molecules associated with junctional complexes and coexpress E- and P-cadherin. However, P-cadherin, plakoglobin and vinculin are the only markers detected in future glomerular cells. We have established a spatiotemporal correlation between the time of appearance and disappearance of junctional complexes as previously described (Saxén and Wartiovaara, Int. J. Cancer 1:271-290, 1966; Saxén et al., Adv. Morphog. 7:251-293, 1968; Reeves et al., Lab. Invest. 39:90-100, 1978), and the expression of their associated molecules. Epithelial cells with stable, typical junctional complexes strongly express the molecules associated with junctions, whereas cells endowed with transient, atypical junctional complexes express low amounts of components associated with junctions. These observations suggest a correlation between the level of expression of these components and an authentic, stable epithelial phenotype.

In the absence of firmly established views on the development of nephropathy, we describe in this paper the embryogenetic and clinical aspects of kidney disease. Congenital reductive nephropathy always arises in the ureteral bud and is determined by two factors, endogenous dysplasia and endogenous obstruction. The nine well-known patterns of disease that may result are described herein. The most important starting points are as follows: (a) A dysplastically disorganized and hence refluxive trigone of the bladder induces, via pyramidal-medullary deficiencies, a defect of the metanephros and thus what we term reflux nephropathy (III-V). BU and PN may supervene postnatally. (b) Similarly, obstruction of the ureteral outlet in the first trimester induces dysplastic ascending nephropathy. (c) The same obstruction beginning in the second trimester induces nondysplastic, purely obstructive nephropathy, characterized by glomerular hypogenesis and hemo-obliterative cirrhosis which varies considerably from stage to stage and from case to case and may go as far as complete loss of the parenchyma. (d) Obstruction of the pyeloureteral junction, occurring late in the embryonic phase and originating outside the urinary system, provides the clearest example of fully developed nondysplastic reductive nephropathy. The lesional process may come to a halt at any time. (e) Coincidence of early embryonic dysplastic-refluxive nephropathy and late embryonic infravesical obstruction (with no causal link) accounts for half the morbidity from valvular disease. The other half results from simple nondysplastic obstruction.

During metanephric development, non-polarized mesenchymal cells are induced to form the epithelial structures of the nephron following interaction with extracellular matrix proteins and factors produced by the inducing tissue, ureteric bud. This induction can occur in a transfilter organ culture system where it can also be produced by heterologous cells such as the embryonic spinal cord. We found that when embryonic mesenchyme was induced in vitro and in vivo, many of the cells surrounding the new epithelium showed morphological evidence of programmed cell death (apoptosis) such as condensed nuclei, fragmented cytoplasm, and cell shrinking. A biochemical correlate of apoptosis is the transcriptional activation of a calcium-sensitive endonuclease. Indeed, DNA isolated from uninduced mesenchyme showed progressive degradation, a process that was prevented by treatment with actinomycin-D or cycloheximide and by buffering intracellular calcium. These results demonstrate that the metanephric mesenchyme is programmed for apoptosis. Incubation of mesenchyme with a heterologous inducer, embryonic spinal cord prevented this DNA degradation. To investigate the mechanism by which inducers prevented apoptosis we tested the effects of protein kinase C modulators on this process. Phorbol esters mimicked the effects of the inducer and staurosporine, an inhibitor of this protein kinase, prevented the effect of the inducer. EGF also prevented DNA degradation but did not lead to differentiation. These results demonstrate that conversion of mesenchyme to epithelial requires at least two steps, rescue of the mesenchyme from apoptosis and induction of differentiation.

Normal development of the human lower urinary tract was studied between the 14th and 20th week of gestation using 3 modes of fixation. Fixation by direct distension provides a high degree of reproducibility of parameters used to study the growth of the fetal bladder. Using this method, fetuses ranging from 12 to 21 weeks gestation were studied. Results obtained demonstrate that the length of the bladder, the inter-ureteric distance, and the distance between the apex of the trigone and the distal tip of the urethra occur in a linear mode. Furthermore, the rate of growth of the male urethra was evidently higher when compared to that of the female from the 12th week of gestation. Data from this work can be used for a more accurate assessment of cases with abnormal lower urinary tract development.

Absence or maldevelopment of the ureteral bud is thought to represent the final pathophysiological pathway resulting in renal anomalies ranging from agenesis to duplication. Little is known about the events preceding anomalous or absent ureteral bud formation. We describe the renal and ureteral anomalies found in a spontaneous murine mutation associated with a short tail: the Danforth or Sd mutation. Thirteen heterozygous pairs of mice were mated. Of 57 near-term progeny 40 had short tails. Microdissection revealed both kidneys and ureters in 35%, neither kidneys nor ureters in 27.5%, absence of the left kidney and ureter in 10%, absence of the right kidney and ureter in 7.5%, and absence of 1 or both kidneys associated with a blind-ending ureter in 20% of the mice. Scanning electron microscopy of gestational day 12 fetuses revealed unilateral or bilateral absence of the metanephros in some embryos, including some with a ureteral bud. Thus, primary absence of the metanephros may have a role in renal agenesis. Additional findings suggest that compensatory renal hypertrophy occurs in utero in the fetuses with unilateral renal agenesis. The morphological abnormalities involving the kidneys in the Sd mutation may represent an excellent model to study the pathophysiology of renal agenesis and mechanisms of normal renal development.

Purpose: To study diagnostic problems encountered by physicians and radiologists in adult females with ureteral ectopia into the urethra. CASE MATERIAL AND METHODS: Retrospective study of 17 localizations in 16 women, 15 to 65 years of age at the time of the definitive diagnosis of duplication of the ipsilateral urinary tract, the ectopia being connected to the upper pelvicalyceal system., Results: Radiological confirmation of the diagnosis had been obtained in 14 cases. The ectopic ureter was thin in 11 cases. In 5 of 6 cases with megaureter, the distension involved only the distal intrapelvic part of the ureter. The ectopic meatus was juxta-cervical in 5 cases, much lower in the other cases. Of the 11 cases investigated by intravenous urography, 8 exhibited severe monocalyceal hydronephrosis of the upper pelvis whereas 6 upper pelvicalyceal systems were dysplastic. The lower pelvicalyceal system was congenitally normal in all cases., Conclusion: Most of the false negative diagnoses of intra-urethral ectopic ureter in adult female result from technically inadequate permicturating urethrocystography. The diagnosis should be evoked, especially in women with recurrent cystitis, on the urographic association of: duplication of the upper urinary tract, dysplastic or chronically distended atrophied upper pelvicalyceal system, pseudo-normal architecture of the lower pelvicalyceal system because of the unusually developed "upper" calyx.

The formation of all organs during embryogenesis, including kidney, is dependent on the timed and sequential expression of a number of polypeptide growth factors. Synthesis and actions of one or more members of the insulin-like growth factor, epidermal growth factor/transforming growth factor-alpha, transforming growth factor-beta, platelet-derived growth factor, fibroblast growth factor, and nerve growth factor families have been characterized in the developing metanephric kidney. Studies originating from a number of laboratories have defined the localization of growth factor mRNAs, receptors and peptides, have delineated patterns of growth factor synthesis, and have established the growth factor dependency of embryonic kidney development. The results of these investigations will be summarized in this editorial review and integrated within the broader context of growth factor cellular physiology and growth factor expression in nonrenal systems.

The role of transforming growth factor-alpha (TGF-alpha) in metanephric development was examined. Metanephroi were removed from 13-day-old rat embryos and grown in organ culture for up to 6 days using serum-free chemically defined media. During this time the metanephroi increased in size and morphological complexity. Messenger RNA for TGF-alpha was present in the renal anlage. Immunoreactive TGF-alpha was produced by metanephroi in vitro and released into culture media. TGF-alpha of metanephric origin coeluted with recombinant human 125I-TGF-alpha after high-performance liquid chromatography of media. In contrast, epidermal growth factor was not detectable. Levels of TGF-alpha were relatively constant during 4 days in culture and averaged approximately 10(-10) M. Growth of the metanephric anlage, arborization of the ureteric bud, and tubulogenesis within the metanephric blastema were inhibited by the addition of anti-TGF-alpha antibodies to organ cultures. These data demonstrate production of TGF-alpha by developing rat metanephroi in organ culture. The peptide is necessary for growth and development in vitro. Our findings suggest a necessary role for TGF-alpha of metanephric origin as a promoter of renal organogenesis in vivo.

Ectopia of the vas deferens into the ureter is a rare occurrence, frequently associated with anorectal anomalies. To date, 20 cases have been reported, accounting for a total of 26 vasoureteral communications, 6 of which are bilateral. Embryologically, ureteral ectopia of the vas deferens may be explained by an underlying defect in the proximal mesonephric duct or an abnormally cranial origin of the ureteric bud. We add the case of a newborn with an ectopic vas terminating into the ureter of a multicystic kidney.

The evaluation of anomalies of the lower urinary tract (ureter, bladder, and urethra) requires high quality ultrasonography, voiding cystourethrography, and, occasionally, intravenous urography and contrast sinography. Infants with these anomalies present because of abnormal intrauterine ultrasonographic examinations, urinary tract infections, or obvious external malformations. With a solid embryologic knowledge of the development of the lower urinary tract the radiologist can tailor the imaging procedures to demonstrate almost all aspects of the anomaly and the presence or absence of frequently associated malformations.

Major controversies still exist regarding the terminology, the etiology and the pathogenesis of congenital obstructive diseases of the ureter. To try to provide some additional information to this controversial subject, a comparative study of ureteral development in rat and human embryos, using light and electron microscopy, has been performed. During fetal development we observed and demonstrated the existence of obstructive phenomena, both at the level of the ureterovesical junction (Chwalla's membrane) and along the ureter. At the end of the embryonic period, the ureter undergoes a physiologic recanalization process.

The myc family of protooncogenes encode similar but distinct nuclear proteins. Since N-myc, c-myc, and L-myc have been found to be expressed in the newborn kidney, we studied their expression during murine kidney development. By organ culture studies and in situ hybridization of tissue sections, we found that each of the three members of the myc gene family shows a remarkably distinct expression pattern during kidney development. It is known that mesenchymal stem cells of the embryonic kidney convert into epithelium if properly induced. We demonstrate the N-myc expression increases during the first 24 h of in vitro culture as an early response to induction. Moreover, the upregulation was transient and expression levels were already low during the first stages of overt epithelial cell polarization. In contrast, neither c-myc nor L-myc were upregulated by induction of epithelial differentiation. c-myc was expressed in the uninduced mesenchyme but subsequently became restricted to the newly formed epithelium and was not expressed in the surrounding loose mesenchyme. At onset of terminal differentiation c-myc expression was turned off also from the epithelial tubules. We conclude that N-myc is a marker for induction and early epithelial differentiation states. That the undifferentiated mesenchyme, unlike stromal cells of later developmental stages, express c-myc demonstrates that the undifferentiated mesenchymal stem cells are distinct from the stromal cells. The most astonishing finding, however, was the high level of L-myc mRNA in the ureter, ureter-derived renal pelvis, papilla, and collecting ducts. In the ureter, expression increased, rather than decreased, with advancing maturation and was highest in adult tissue. Our results suggest that each of the three members of the myc gene family are involved in quite disparate differentiation processes, even within one tissue.

We report two cases of urinary incontinence secondary to ectopic ureteral implantation with pyeloureteral duplication in a 14 and 18 year-old girls. Our observations are discussed with the review of the world publication about this data.

A hypothesis for the embryogenesis of lower ureteral anomalies invokes variations in location and number of ureteral buds on the mesonephric duct. Such vagaries determine the length of the common nephric duct and the time of meeting of the ureteral bud (or buds) with the urogenital sinus. These factors in turn affect the density of the mesenchymal tissue and its mass in relation to the adjoining structures and, ultimately, the musculature of the trigone as well as the level of the ureteral hiatus and the musculature of the bladder base. Primary reflux, ureteral ectopy, ureteral duplication, ureterocele, functional ureteral obstruction, and congenital strictures are viewed and possibly explained in the light of the embryonal variations mentioned.

32 cases of single ectopic ureter have been reviewed. The more remote the ectopic orifice opens from its normal position the more severe were the associated renal anomalies. In the great majority of cases, the corresponding kidney was dysplastic and radiographically functionless. An embryological explanation is proposed to account for the association of single ectopic ureter with a dysplastic kidney. Clinical symptomatology was dribbling incontinence in most female cases and various urogenital complaints in male. An accurate preoperative diagnosis is usually reached with a pyelogram and micturating cystogram. In some female cases a vaginogram or direct puncture and opacification of a vaginal cystic mass may be contributive. In the male, a radiological non-functioning kidney on one side of the urogram associated with a cystic mass palpated above the prostate is pathognomonic of an ectopic ureter opening in the seminal tract. Deferentography may confirm this diagnosis. Treatment of the condition is surgical. In the great majority of cases nephroureterectomy is required. In the male, the abnormal seminal tract involved in this complex malformation should also be removed.

The ureteral bud in the embryonic kidney grows and branches dichotomously for 15 generations. This branching tree is modified by a series of narrowings and expansions and becomes the ureter, the renal pelvis, the calyces, and the collecting tubules. Simultaneously, the ureteral bud induces the formation of nephrons. If many of the renal cystic diseases and congenital dilatations of the renal pelvis and ureter are viewed as a series of growth disturbances along the branching ureteral bud, their morphology and pathophysiology become clarified even though their etiology is often not known.

We have experienced 7 cases of multicystic kidney. The latest two cases, etiologically of interest, are reported herein with special reference to its embryogenesis. Case 6: A 4-year-old girl was referred to our clinic for further evaluation of mild azotemia and nonvisualization of left kidney. Left kidney was strongly thought to be multicystic kidney from abdominal CT, whereas her contralateral kidney exhibited hydrocalycosis resembling infundibular stenosis with diminished calyceal numbers. Nephrectomy of her left kidney was performed and histological studies confirmed renal dysplasia (primitive duct, metaplastic cartilage, etc.). Case 7: A 7-year-old girl was referred to Hakodate Kyokai Hospital for the evaluation of azotemia and low stature. Her right kidney was not visualized on IVP and her left kidney exhibited hydronephrosis with diminished calyceal numbers. Her right kidney was diagnosed as multicystic kidney on CT-scan. Pyeloplasty of her left kidney was performed. Multicystic kidney is a rather rare congenital disease. Association of various anomalies in contralateral kidney has been emphasized as well as the notion that infundibulopelvic stenosis is a linked in the clinical spectrum extending from cystic dysplasia of the kidney to hydronephrosis. Our last two cases seem to be included in this category of obstruction theory. As shown by microdissection technique (Potter), however, severe ampullary inhibition early in fetal life is also an attractive hypothesis. Diminished calyceal number of contralateral kidneys seen in our recent two cases is compatible with possibility of ampullary damage. Recent experimental study also showed that renal dysplasia is not solely caused by simply mechanical obstruction to urinary drainage, even when the obstruction is imposed at an early stage of renal development.

83 albino rat embryos were used to investigate and ascertain the presence of the ureteric membrane closing the mouth of the primitive ureterovesical opening. The membrane is found to be derived from the stratified etithelium lining the urogenital sinus and later the developing urinary bladder. It progressively thins out and bulges in the bladder cavity as a result of the increasing functional differentiation and activity of the developing kidney, where the excreted urine dilates the lower end of the ureter till it forms a small cyst-like dilatation before the membrane finally ruptures. The destruction of the ureteric membrane occurs caudal to its center and is immediately followed by dilatation of the bladder cavity and differentiation of mits musculature and lining epitherlium.

The cause of ureteral ectopia in a single nonduplicated system is probably an abnormally high origin of the ureteral bud on the mesonephric duct. In the male patient with vague and unexplained lower urinary tract symptoms, extravesical ureteral ectopia must be considered, especially in prepubertal males with epididymitis and a solitary kidney. Physical examination, seminal vesiculography with delayed films, and voiding cystourethrogram should provide a diagnosis.

Female Swiss mice (25-30 g) received a single subcutaneous injection of 200 mug nucleotoxic substance (chloraminophen) on day 11 of pregnancy. The fetuses taken from the treated mother on day 18 show a significant lack of development and urinary anomalies, such as ureterohydronephrosis (26%) and renal agenesis (few cases). Ureterohydronephrosis seems to be caused by lacking development of the ureterovesical junction region.

The structures of the ureter, ureterovesical junction, bladder and sphincteric urethra were investigated histologically in 17 human fetuses (from 3rd to 21st weeks) and 2 neonates, with particular emphasis on their muscular development. The differentiation of ureteral muscle begins from the upper part of the ureter at the 12th week and muscle bundles run spirally. The purely longitudinal intramural ureteral muscle differentiates much later than the upper ureteral muscle and begins to form muscle bundles at the 17th week. The deep periureteral sheath and the trigonal muscle differentiate at an almost similar pace to the intramural ureteral muscle. The detrusor muscle begins to differentiate from the apical dome of the bladder at the 7th week. Distinct superficial periureteral sheath is also seen around the 12th week. The urethral striated muscle is recognized at the 8th week. It starts to develop in the anterior wall of the urethra as a dense cellular accumulation which eventually extends caudolaterally to form a U-shaped figure. The urethral smooth muscle starts its differentiation between the 9th and 11th weeks inside the urethral striated muscle.

A unique case of left ureteral opening into a seminal vesicle, ipsilateral renal hyperplasia and crossed ectopia of the seminal vesicles is reported. This 24-year-old white man underwent a nephroureterectomy for relief of symptoms of lower urinary tract infection. The embryological development of this abnormality is discussed briefly.