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PubMed1992

Morphogenesis of African swine fever virus in monkey kidney cells after reversible inhibition of replication by cycloheximide.

The late cytoplasmic phases of African swine fever virus (ASFV) morphogenesis in monkey kidney cells have been studied by transmission electron microscopy, focusing attention on the synthesis of viral envelopes. Morphogenesis was studied after reversible cycloheximide blockage of monkey kidney cells infected with ASFV. ASFV appears to synthesize its external and internal envelopes within the cellular cytoplasm, at the same time as the capsid is formed, with intracellular and extracellular virions showing similar structure and polypeptide composition.

African Swine Fever Virus↗
PubMed1997

Proliferation, differentiation and morphogenesis of fetal rat glandular stomach transplanted under the kidney capsule of syngeneic hosts.

Undifferentiated glandular stomach tissue fragments from 16.5-day fetal rats were transplanted under the kidney capsule of syngeneic adult rats, and the proliferation, differentiation and morphogenesis of the transplanted tissues were investigated. Gastric epithelial cells began to invaginate 3-4 days after the transplantation and immature glands were formed after 1 week. During the period, there was a gradual increase in the expression of pepsinogen and cathepsin E, markers of cytodifferentiation of the stomach epithelia, both at protein and mRNA levels. Cathepsin E was weakly expressed in undifferentiated gastric epithelial cells at 16.5 days of gestation, and a higher level of the expression was observed in differentiated epithelia of the transplants. In contrast, the pepsinogen-producing cells first appeared around days 3-4 after transplantation and gradually increased in number to about 30% of the epithelial cells and became localized at the bottom of the gland. During the period of the experiment up to 1 month, the pepsinogen-producing cells were all positive for class III mucin and cathepsin E, indicating the immature character of these cells. In addition, no parietal cells were observed. When the tissue fragments were transplanted into adrenalectomized animals, the epithelial differentiation and morphogenesis was suppressed, but its proliferation was enhanced. The observed changes were reversed by hydrocortisone replacement. These results suggest that the development of the 16.5-day fetal stomach is regulated intrinsically to a certain extent by the genetic program of the cells involved and various gastric functions develop in the absence of luminal stimulation, stage-specific systemic hormonal change, neuronal regulation or other systemic influences, and that glucocorticoids modulate the developmental program of the fetal stomach tissues.

Adrenalectomy↗
PubMed1999

Branching morphogenesis independent of mesenchymal-epithelial contact in the developing kidney.

Whether mesenchymal-epithelial interactions leading to branching morphogenesis in developing epithelial tissues such as the kidney require direct cell-cell contact or are due to soluble mediators elaborated by the inducing tissue has been the subject of much debate. Here we demonstrate that ureteric bud (UB) epithelium, from which the kidney collecting system and upper urinary tract are derived, can undergo impressive three-dimensional branching morphogenesis when cultured in the appropriate extracellular matrix context in the absence of direct contact with mesenchymal tissue, indicating that the program for branching morphogenesis is inherent to the UB. Both a soluble factor in BSN cell-conditioned medium (BSN-CM) derived from an immortalized cell line thought to originate in the early metanephric mesenchyme and glial cell line-derived neurotrophic factor (GDNF) were required for early and later events in branching morphogenesis. In the absence of BSN-CM, the isolated UB did not survive; a similar result was obtained in the presence of neutralizing antibodies against glial cell line-derived neurotrophic factor. Preliminary analysis of key activity present in BSN-CM indicates that it is a heat-sensitive, heparin-binding factor with a probable molecular mass greater than 100 kDa. When the in vitro cultured UB was recombined with freshly isolated metanephric mesenchyme, nephric units were induced in the mesenchyme, and the UB branches underwent elongation. Our data suggest that, although UB branching morphogenesis per se does not require direct mesenchymal contact, such contact may play a key role in regulating branch elongation and establishing the pattern of branching. The results also suggest an approach to in vitro engineering of nephron.

Animals↗
PubMed2006

Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1.

Branching of ureteric bud-derived epithelial tubes is a key morphogenetic process that shapes development of the kidney. Glial cell line-derived neurotrophic factor (GDNF) initiates ureteric bud formation and promotes subsequent branching morphogenesis. Exactly how GDNF coordinates branching morphogenesis is unclear. Here we show that the absence of the receptor tyrosine kinase antagonist Sprouty1 (Spry1) results in irregular branching morphogenesis characterized by both increased number and size of ureteric bud tips. Deletion of Spry1 specifically in the epithelium is associated with increased epithelial Wnt11 expression as well as increased mesenchymal Gdnf expression. We propose that Spry1 regulates a Gdnf/Ret/Wnt11-positive feedback loop that coordinates mesenchymal-epithelial dialogue during branching morphogenesis. Genetic experiments indicate that the positive (GDNF) and inhibitory (Sprouty1) signals have to be finely balanced throughout renal development to prevent hypoplasia or cystic hyperplasia. Epithelial cysts develop in Spry1-deficient kidneys that share several molecular characteristics with those observed in human disease, suggesting that Spry1 null mice may be useful animal models for cystic hyperplasia.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The renin-angiotensin system in the development of the congenital anomalies of the kidney and urinary tract.

PURPOSE OF REVIEW: Recognition of the dramatically expanded functional repertoire of the renin-angiotensin system now includes a role in morphogenesis of the kidney and urinary tract. On the basis of published data, the article presents formulations of mechanisms through which the system operates. RECENT FINDINGS: Studies in humans and animals carrying defective angiotensin-related genes have provided unequivocal evidence that the renin-angiotensin system is involved in the normal development of both the kidney and the urinary tract. Angiotensin exerts its function through at least two different types of receptors, AT1 and AT2. AT1 mediates establishment of the ureteral peristaltic machinery, while AT2 mediates the early kidney and urinary tract morphogenesis. Disruption in receptor functions promotes development of congenital anomalies of the kidney and urinary tract. SUMMARY: Angiotensin is involved in multiple steps of normal development of the kidney and urinary tract through two types of receptors. This takes place in concert with other functionally overlapping genes.

Animals↗
PubMed2000

Role of fibronectin deposition in branching morphogenesis of Madin-Darby canine kidney cells.

BACKGROUND: Madin-Darby canine kidney (MDCK) epithelial cells grown in collagen gels in the presence of hepatocyte growth factor (HGF) form branching tubules. The tubule-lining epithelial cells are polarized with the basolateral surface in contact with the collagen gel and the apical surface facing the lumen. To delineate whether MDCK branching tubules construct the basal lamina, we characterized the composition of the extracellular matrix deposited by MDCK tubules. The tubule-lining cells produced an apparently incomplete basal lamina containing a discontinuous laminin substratum. In addition, a thick layer of fibronectin surrounded the basal cell surface of the branching tubule. In an attempt to delineate the role of fibronectin deposition in branching morphogenesis, we conducted this study. METHODS: MDCK cells cultured in collagen gel were employed. We first used arginine-glycine-aspartate peptides containing disintegrin rhodostomin to disturb the interactions between fibronectin and cell surface integrins. Furthermore, we established several stable transfectants expressing fibronectin antisense RNA to examine the role of fibronectin in branching morphogenesis directly. RESULTS: Rhodostomin inhibited the formation of branching tubules. The transfectants expressing fibronectin antisense RNA exhibited relatively lower levels of synthesized fibronectin and markedly diminished growth rates of branching tubules than the control clone. An inhibition of branching morphogenesis induced by the overexpression of fibronectin antisense RNA was manifested by the decrease in cell growth rates and cell migration. CONCLUSION: These results indicate that the deposition of fibronectin underlying the tubule-lining epithelium serves to enhance cell proliferation and migration, and hence facilitates the branching tubulogenesis of MDCK cells.

Animals↗
PubMed2005

Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis.

Bone morphogenetic protein 7 (BMP7) stimulates renal branching morphogenesis via p38 mitogen-activated protein kinase (p38(MAPK)) and activating transcription factor 2 (ATF-2) (M. C. Hu, D. Wasserman, S. Hartwig, and N. D. Rosenblum, J. Biol. Chem. 279:12051-12059, 2004). Here, we demonstrate a novel role for integrin-linked kinase (ILK) in mediating renal epithelial cell morphogenesis in embryonic kidney explants and identify p38(MAPK) as a target of ILK signaling in a cell culture model of renal epithelial morphogenesis. The spatial and temporal expression of ILK in embryonic mouse kidney cells suggested a role in branching morphogenesis. Adenovirus-mediated expression of ILK stimulated and expression of a dominant negative ILK mutant inhibited ureteric bud branching in embryonic mouse kidney explants. BMP7 increased ILK kinase activity in inner medullary collecting duct 3 (IMCD-3) cells, and adenovirus-mediated expression of ILK increased IMCD-3 cell morphogenesis in a three-dimensional culture model. In contrast, treatment with a small molecule ILK inhibitor or expression of a dominant negative-acting ILK (ILK(E359K)) inhibited epithelial cell morphogenesis. Further, expression of ILK(E359K) abrogated BMP7-dependent stimulation. To investigate the role of ILK in BMP7 signaling, we showed that ILK overexpression increased basal and BMP7-induced levels of phospho-p38(MAPK) and phospho-ATF-2. Consistent with its inhibitory effects on IMCD-3 cell morphogenesis, expression of ILK(E359K) blocked BMP7-dependent increases in phospho-p38(MAPK) and phospho-ATF-2. Inhibition of p38(MAPK) activity with the specific inhibitor, SB203580, failed to inhibit BMP7-dependent stimulation of ILK activity, suggesting that ILK functions upstream of p38(MAPK) during BMP7 signaling. We conclude that ILK functions in a BMP7/p38(MAPK)/ATF-2 signaling pathway and stimulates epithelial cell morphogenesis.

Activating Transcription Factor 2↗
PubMed1980

Induction of a basement membrane glycoprotein in embryonic kidney: possible role of laminin in morphogenesis.

The glycoprotein laminin is found exclusively in the basement membranes of adult tissues, not in the mesenchymal stroma. We studied the appearance and distribution of laminin during the early formation of kidney tubules in mouse embryos and in an in vitro transfilter model system. In immunofluorescence using affinity-purified antibodies, the distribution of laminin showed a clear correlation, both spatially and temporally, to the early stages of tubule formation. In vivo, laminin was first detected in a punctate pattern in areas where the pretubular aggregates form; later, it became confined to the basement membranes of the tubules. In experiments in vitro, the nephrogenic mesenchyme was found to form tubules after 12-24 hr of transfilter contact with the inductor. The first laminin spots were found after 12 hr of culture, 24 hr before overt morphogenesis. As the mesenchymal cells began to aggregate and elongate (at 36 hr), laminin was detected in those cells destined to become epithelial, and at 48 hr it was not found in cells remaining in the stroma. In more mature tubules (at 72 hr), laminin was seen as a sharp band in the basement membranes. It is suggested that laminin is involved in the increased cell adhesiveness during the early aggregation of the nephrogenic mesenchyme.

Animals↗
PubMed2005

BMP4 substitutes for loss of BMP7 during kidney development.

Functional inactivation of divergent bone morphogenetic proteins (BMPs) causes discrete disturbances during mouse development. BMP4-deficient embryos display mesodermal patterning defects at early post-implantation stages, whereas loss of BMP7 selectively disrupts kidney and eye morphogenesis. Whether these distinct phenotypes simply reflect differences in expression domains, or alternatively intrinsic differences in the signaling properties of these ligands remains unknown. To address this issue, we created embryos exclusively expressing BMP4 under control of the BMP7 locus. Surprisingly, this novel knock-in allele efficiently rescues kidney development. These results demonstrate unequivocally that these structurally divergent BMP family members, sharing only minimal sequence similarity can function interchangeably to activate all the essential signaling pathways for growth and morphogenesis of the kidney. Thus, we conclude that partially overlapping expression patterns of BMPs serve to modulate strength of BMP signaling rather than create discrete fields of ligands with intrinsically different signaling properties.

Animals↗
PubMed2004

Regulation of ureteric bud branching morphogenesis by sulfated proteoglycans in the developing kidney.

Glycosaminoglycans in the form of heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG) are required for normal kidney organogenesis. The specific roles of HSPGs and CSPGs on ureteric bud (UB) branching morphogenesis are unclear, and past reports have obtained differing results. Here we employ in vitro systems, including isolated UB culture, to clarify the roles of HSPGs and CSPGs on this process. Microarray analysis revealed that many proteoglycan core proteins change during kidney development (syndecan-1,2,4, glypican-1,2,3, versican, decorin, biglycan). Moreover, syndecan-1, syndecan-4, glypican-3, and versican are differentially expressed during isolated UB culture, while decorin is dynamically regulated in cultured isolated metanephric mesenchyme (MM). Biochemical analysis indicated that while both heparan sulfate (HS) and chondroitin sulfate (CS) are present, CS accounts for approximately 75% of the glycosaminoglycans (GAG) in the embryonic kidney. Selective perturbation of HS in whole kidney rudiments and in the isolated UB resulted in a significant reduction in the number of UB branch tips, while CS perturbation has much less impressive effects on branching morphogenesis. Disruption of endogenous HS sulfation with chlorate resulted in diminished FGF2 binding and proliferation, which markedly altered kidney area but did not have a statistically significant effect on patterning of the ureteric tree. Furthermore, perturbation of GAGs did not have a detectable effect on FGFR2 expression or epithelial marker localization, suggesting the expression of these molecules is largely independent of HS function. Taken together, the data suggests that nonselective perturbation of HSPG function results in a general proliferation defect; selective perturbation of specific core proteins and/or GAG microstructure may result in branching pattern defects. Despite CS being the major GAG synthesized in the whole developing kidney, it appears to play a lesser role in UB branching; however, CS is likely to be integral to other developmental processes during nephrogenesis, possibly involving the MM. A model is presented of how, together with growth factors, heterogeneity of proteoglycan core proteins and glycosaminoglycan sulfation act as a switching mechanism to regulate different stages of the branching process. In this model, specific growth factor-HSPG combinations play key roles in the transitioning between stages and their maintenance.

Animals↗
PubMed1999

The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis.

Epithelial-mesenchymal interactions are required for the development of all solid organs but few molecular mechanisms that underlie these interactions have been identified. Pod1 is a basic-helix-loop-helix (bHLH) transcription factor that is highly expressed in the mesenchyme of developing organs that include the lung, kidney, gut and heart and in glomerular visceral epithelial cells (podocytes). To determine the function of Pod1 in vivo, we have generated a lacZ-expressing null Pod1 allele. Null mutant mice are born but die in the perinatal period with severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli. Although Pod1 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in the adjacent epithelia and include abnormalities in epithelial differentiation and branching morphogenesis. Pod1 therefore appears to be essential for regulating properties of the mesenchyme that are critically important for lung and kidney morphogenesis. Defects specific to later specialized cell types where Pod1 is expressed, such as the podocytes, were also observed, suggesting that this transcription factor may play multiple roles in kidney morphogenesis.

Alleles↗
PubMed2000

Age effect of type I collagen on morphogenesis of Mardin-Darby canine kidney cells.

BACKGROUND: Mardin-Darby canine kidney (MDCK) cells cultured in hydrated collagen gels develop simple epithelial cysts or branching tubules, depending on the presence of hepatocyte growth factor (HGF). Constituents of extracellular matrix can modulate the morphogenesis of MDCK cells. Collagen is one of the few well-defined structural entities that display gross structural changes with aging. This study was conducted to delineate the effects of age-induced changes of collagen on the morphogenesis of MDCK cells cultured in collagen gel. METHODS: We employed Y224 and MDCK clone II 3B5 cells to study cystogenesis and branching tubulogenesis, respectively. Cells were cultured in three-dimensional collagen gels prepared from 1-, 4-, 8-, and 16-month-old rat tail tendons, and their capacity to develop cysts or branching tubules was assessed. We also analyzed the compositions and physical structures of collagen of various ages. RESULTS: Y224 cells developed generally larger spherical cysts in collagen gels prepared from rats that were more than four months old. The ratio of apoptosis of cells cultured in one-month-old collagen gel was markedly higher than in the gel of older ages. The results were consistent with the observations that collagen gel overlay-induced apoptosis of Y224 cells in one-month-old collagen was higher than that in older collagen. On the other hand, 3B5 cells exhibited a remarkable scattering morphology when cultured in one- or four-month-old collagen gel with HGF. In contrast, 3B5 cells exhibited more intercellular adhesion and were organized into branching tubule structures only in the collagen gel that was more than eight months old. The differences in morphogenesis could be explained by the observations that collagen of younger ages exerted markedly higher HGF-triggered migration capability than collagen of older ages. CONCLUSIONS: Age-related alterations in collagen influence epithelial cell morphogenesis via regulation of cell apoptosis, proliferation, and/or motility.

Acids↗
PubMed2004

Morphogenesis of fowlpox virus in a baby hamster kidney cell line.

Fowlpox virus (FWPV) recombinant vaccines are presently being tested as an antihuman immunodeficiency virus vaccine for humans. However, biosafety, as well as the morphogenesis of FWPV in mammalian cells, are not well understood. Currently, electron microscopy is the method of choice for analyzing virus morphogenesis in cell lines. In this study, four different electron microscopic techniques were used to study FWPV morphogenesis in the Syrian baby hamster kidney (BHK-21) cell line: direct negative stain electron microscopy, ultrathin section transmission electron microscopy, cryoimmunoelectron microscopy, and scanning electron microscopy. The study showed matured viruses, as well as other stages of fowlpox virus maturation, in BHK-21 cells that led to productive virus multiplication. A number of virus-containing vesicles and plasma membrane-associated mature viruses at an early stage in the budding process were observed. In addition, intracellular mature virus was observed in layers of the trans-Golgi network, a characteristic of intracellular mature virus wrapping that results in the formation of intracellular enveloped virus. The size and morphology of FWPV observed in this study are comparable with previously published data. This study presents the first morphological evidence for the release of FWPV by budding in BHK-21 cells.

Animals↗
PubMed2004

Rescue of defective branching nephrogenesis in renal-coloboma syndrome by the caspase inhibitor, Z-VAD-fmk.

In renal-coloboma syndrome (RCS), null mutations of the PAX2 gene cause renal hypoplasia due to a congenital deficit of nephrons; affected individuals may develop renal insufficiency in childhood. During normal kidney development, PAX2, is expressed at high levels throughout the arborizing ureteric bud (UB); recent observations suggest that one of its key roles is to suppress apoptosis in this collecting duct lineage. The authors hypothesized that increased UB cell apoptosis due to PAX2 haploinsufficiency must directly influence the rate of branching morphogenesis in developing kidney and the number of nephrons that can be formed before birth, when nephrogenesis in humans comes to an end. If so, the authors reasoned that caspase inhibitors might be used to suppress unwanted UB cell apoptosis during kidney development in Pax2(1Neu) mutant mice and rescue the genetic UB branching defect. E17.5 kidneys from Pax2(1Neu) mutant mice had smaller (-25%) longitudinal cross-sectional area and 3.5-fold increase in collecting duct cell apoptosis versus wild-type littermates; mutant E13.5 kidney explants allowed to arborize for 50 h in vitro had 18% fewer terminal branches than wild-types. However, exposure to the caspase inhibitor, Z-VAD-fmk (25 micro M), significantly increased terminal branch number in mutant explants (23%). It also increased branching in wild-type explants, apparently reflecting an effect of Z-VAD-fmk on basal apoptosis induced by ex vivo culture conditions. Similarly, when pregnant mice were injected daily with Z-VAD-fmk (10 micro g/g weight from E10.5 to E17.5), apoptosis of Pax2(1Neu) fetal collecting duct cells was suppressed to 40% of untreated mutants; by E14, terminal branch number was increased to 152% that of untreated litters. These studies support the hypothesis that PAX2 normally optimizes the rate of branching morphogenesis in fetal kidney by suppressing UB apoptosis. Furthermore, it suggests that caspase inhibitors can rescue the branching defect caused by PAX2 mutations.

Amino Acid Chloromethyl Ketones↗
PubMedDate not supplied

Expression of fetal kidney growth factors in a kidney tumor line: role of FGF2 in kidney development.

To identify growth factors which may play a role in kidney organogenesis, we have analyzed culture supernatants from the pediatric kidney tumor cell line G401. G401 cells were found to secrete fibroblast growth factor 2 (FGF2), a potent mitogen for mesenchymal cells, OP-1/BMP7, an epithelial cell growth inhibitor, and midkine (MK). Northern blotting confirmed expression of FGF2, OP-1/BMP7 and MK mRNA, as well as Wnt5A mRNA in G401 cells. In situ hybridization and immunocytochemistry on human fetal kidney demonstrated FGF2 expression in epithelial cells of the branching ureteric bud epithelium, nephron precursors ("S-shaped bodies"), proximal tubule epithelium and the parietal epithelium of the glomerulus. FGF2 protein in condensed "caps" of induced mesenchymal cells was also detected by immunocytochemistry. FGF2 protein was found to be concentrated in nuclei, particularly in proximal tubule epithelial cells. Recombinant FGF2 was found to act as a mitogen on primary mouse fetal kidney cell cultures. The results demonstrate G401 cells secrete a variety of fetal kidney growth factors and that FGF2 may act as a mitogen for fetal kidney cells and thus could play a role in the morphogenesis of the kidney.

Animals↗
PubMed1983

[Characteristics of kidney involvement in disseminated intravascular coagulation (morphogenesis of cortical necrosis)].

Morphological examinations of 72 autopsy observations of the disseminated intravascular blood coagulation (DIVBC) syndrome (a combination of microthrombosis in renal glomeruli, adrenals, gastrointestinal tract and other organs with the hemorrhagic syndrome) led to a conclusion on the role of DIVBC in the formation of cortical renal necroses. All the observations presented capillary thrombosis of the renal glomeruli the extent and dissemination of which had influenced the size of cortical necroses. Cortical ischemia in early stages is manifested by nephrothelium dystrophy followed at 3-5 days by the development of necrosis of the tubules, glomeruli, and stroma. The formed cortical necroses of the kidneys (CNK) are demarkated, their healing occurs at the expense of the interstitial tissue, whose cells proliferate, and later collagen genesis is observed. Scars from CNK have been shown to contain tubules with an undifferentiated epithelium.

Adult↗