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PubMed1983

Recent progress towards understanding the roles of the basement membrane in development.

A brief description of the structure of basement membranes is presented including results of immunocytochemical investigations. A number of developmental events are considered in which the basement membrane has been implicated in the regulation of morphogenesis. One of the clearest developmental functions appears to be the maintenance of the lobular morphology of glandular epithelia, where the basement membrane supplies a supportive scaffold. The contributions of the glycoproteins laminin and fibronectin to basement membrane function are discussed with reference to potential roles for this structure as a substratum for morphogenetic cell migrations and as a mediator of inductive interactions in embryogenesis. Examples used to illustrate these proposals include the mesodermal migrations of gastrulation, kidney tubule morphogenesis, and limb bud development. Evidence from these and other sources lend support to current view for an active and changing role for the basement membrane in the epithelial-mesenchymal interactions of embryonic development.

Animals↗
PubMed1979

Vaccinia virus replication. I. Requirement for the host-cell nucleus.

Using cytochalasin B-induced enucleation techniques, we examined the ability of vaccinia virus to replicate in the absence of the host-cell nucleus in several mammalian cell lines. It was found that virus-infected enucleated cells (cytoplasts) prepared from BSC-40, CVC, and L cells were incapable of producing infectious progeny virus. The nature of this apparent nuclear involvement was studied in detail in BSC-40 cells. Modulations designed to maximize cytoplast integrity and longevity, such as reduction of the growth temperature and initial multiplicity of infection, did not improve virus growth in cytoplasts. Sodium dodecyl sulfate-polyacrylamide gel analysis of the [(35)S]methionine pulse-labeled proteins synthesized in vaccinia virus-infected cytoplasts demonstrated that both early and late viral gene products were being expressed at high levels and with the proper temporal sequence. Vaccinia virus cytoplasmic DNA synthesis, as measured by [(3)H]thymidine incorporation, peaked at 3 h postinfection and was 70 to 90% of control levels in cytoplasts. However, in the cytoplasts this DNA was not converted to a DNase-resistant form late in infection, which was consistent with the failure to isolate physical particles from infected cytoplasts. Treatment of vaccinia virus-infected cells with 100 mug of rifampin/ml from 0 to 8 h to increase the pools of viral precursors, followed by subsequent removal of the drug, resulted in a threefold increase virus yield. This treatment had no effect on virus-infected cytoplasts. Finally, vaccinia virus morphogenesis was studied under an electron microscope in thin sections of virus-infected cells and cytoplasts which had been prepared at various times during a single-step growth cycle. It was apparent that, although early virus morphogenetic forms appeared, there was no subsequent DNA condensation or particle maturation in the cytoplasts. These results suggest that vaccinia virus requires some factor or function from the host-cell nucleus in order to mature properly and produce infectious progeny virus.

Animals↗
PubMed1995

Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells.

Signals transduced by the met tyrosine kinase, which is the receptor for scatter factor/hepatocyte growth factor, are of major importance for the regulation of epithelial cell motility, morphogenesis, and proliferation. We report here that different sets of tyrosine residues in the cytoplasmic domain of the met receptor affect signal transduction in epithelial cells in a positive or negative fashion: mutation of the C-terminal tyrosine residues 13-16 (Y1311, Y1347, Y1354, and Y1363) reduced or abolished ligand-induced cell motility and branching morphogenesis. In contrast, mutation of the juxtamembrane tyrosine residue 2 (Y1001) produced constitutively mobile, fibroblastoid cells. Furthermore, the gain-of-function mutation of tyrosine residue 2 suppressed the loss-of-function mutations of tyrosine residue 15 or 16. The opposite roles of the juxtamembrane and C-terminal tyrosine residues may explain the suggested dual function of the met receptor in both epithelial-mesenchymal interactions and tumor progression.

Amino Acid Sequence↗
PubMed1993

Modulation of epithelial morphogenesis and cell fate by cell-to-cell signals and regulated cell adhesion.

Cell-cell and cell-extracellular matrix (ECM) interactions control many developmental decisions of epithelial cell fate and morphogenesis. Protein tyrosine kinases are one class of regulatory molecules that have been implicated in the modulation of these processes. Several protein tyrosine kinases co-localize with cell-cell (cadherin) and cell-ECM (integrin) adhesion molecules at specific adhesion domains of epithelial cells. Protein tyrosine kinases may regulate epithelial development by modulating cell-cell and cell-ECM interactions and by relaying signals initiated by these interactions to other cellular components that determine cell structure and function.

Animals↗
PubMed2003

Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development.

Reciprocal cell-cell interactions between the ureteric epithelium and the metanephric mesenchyme are needed to drive growth and differentiation of the embryonic kidney to completion. Branching morphogenesis of the Wolffian duct derived ureteric bud is integral in the generation of ureteric tips and the elaboration of the collecting duct system. Wnt11, a member of the Wnt superfamily of secreted glycoproteins, which have important regulatory functions during vertebrate embryonic development, is specifically expressed in the tips of the branching ureteric epithelium. In this work, we explore the role of Wnt11 in ureteric branching and use a targeted mutation of the Wnt11 locus as an entrance point into investigating the genetic control of collecting duct morphogenesis. Mutation of the Wnt11 gene results in ureteric branching morphogenesis defects and consequent kidney hypoplasia in newborn mice. Wnt11 functions, in part, by maintaining normal expression levels of the gene encoding glial cell-derived neurotrophic factor (Gdnf). Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching. Conversely, Wnt11 expression is reduced in the absence of Ret/Gdnf signaling. Consistent with the idea that reciprocal interaction between Wnt11 and Ret/Gdnf regulates the branching process, Wnt11 and Ret mutations synergistically interact in ureteric branching morphogenesis. Based on these observations, we conclude that Wnt11 and Ret/Gdnf cooperate in a positive autoregulatory feedback loop to coordinate ureteric branching by maintaining an appropriate balance of Wnt11-expressing ureteric epithelium and Gdnf-expressing mesenchyme to ensure continued metanephric development.

Alleles↗
PubMed1970

Morphogenesis of respiratory syncytial virus in a green monkey kidney cell line (Vero).

The structure and morphogenesis of respiratory syncytial (RS) virus particles in a green monkey kidney cell line (Vero) were examined. Infected cells contained dense intracytoplasmic inclusions composed of filamentous structures. In places where inclusion material was associated with membranes, structural modifications were induced. There was a thickening of the membrane and an addition of projections 12 to 15 nm in length. The same changes were most frequently observed after association of isolated filamentous structures with the cytoplasmic membrane. The budding-off process was clearly visualized. The diameter of mature virus particles varied between 90 and 130 nm and that of the internal component varied between 11 and 15 nm. The similarities between ultrastructural features of cells infected with RS virus and pneumonia virus of mice are pointed out. It is proposed that these two viruses should be classified together in a third subgroup of myxoviruses.

Animals↗
PubMed1979

Morphogenesis of foot-and-mouth disease virus. I. Role of procapsids as virion Precursors.

The role of procapsids during foot-and-mouth disease virus multiplication was studied on infected BHK-21 cells. Purified virus and procapsids were obtained by treating the infected cytoplasmic extracts with RNase and EDTA. The synthesis of virus, procapsids, and total particles was determined in pulse-chase experiments. A precursor-product relationship between procapsids and virions was obtained. The results show that the rate of synthesis of total particles (virus + procapsids) was linear from the addition of the label and was identical to that corresponding to virions. Therefore, the speed of the morphogenetic process as well as the existence of a precursor pool of structural proteins was established. Furthermore, the rate of virus synthesis from procapsids was identical to the rate of synthesis of procapsids from their structural precursors. A quantitative recovery of label from procapsids into virions was obtained by the use of cycloheximide or tosyl-lysine chloromethyl ketone. Under these conditions, virus synthesis proceeds, indicating that these drugs do not affect the morphogenetic step studied in this paper.

Animals↗
PubMed2006

The role of obesity and its bioclinical correlates in the progression of chronic kidney disease.

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.

Animals↗
PubMed2001

Recombinant proteins produced by vaccinia virus vectors can be incorporated within the virion (IMV form) into different compartments.

Vaccinia virus (VV) is one of the largest and most complex of animal viruses, with a virion that contains about 100 different polypeptides. Assembly of the viral proteins occurs in discrete cytoplasmic sites leading to formation of two infectious forms, an abundant (>90%) intracellular mature virus (IMV) with an envelope, and a minor extracellular enveloped virus (EEV) with an extra membrane acquired from the trans-Golgi network. It has been shown that while EEV contains in the outer membrane cellular proteins probably acquired during virus release from cells, however, IMV exclude host proteins during assembly. Since VV recombinants (VVr) expressing genes of interest are candidates as potential vaccines against pathogens and cancer, it becomes important to know if VVr can acquire foreign proteins during morphogenesis. In this investigation we show that purified virions (IMVs) from VVr can incorporate foreign proteins into different sites in the virus particle. By sequential fractionation of virion compartments with detergents, we found foreign proteins in the lipid envelope (cytokine IL-12 and CS antigen of Plasmodium yoelii), as part of a protein matrix-like membrane (HIV-1 gp41 of env), or more closely associated with the core containing the DNA complexes (HIV-1 gp160; a multiepitopic protein with the V3 loop of HIV-1 Env from different isolates, and beta-galactosidase). Similar findings were observed with purified virions derived from the WR strain as well as from the highly attenuated modified vaccinia virus Ankara (MVA) strain. These observations should be taken into consideration when VVr are used in clinical trials or in other vaccination approaches.

Animals↗
PubMed1997

Development of the kidney vasculature.

Renal vascularization and nephrogenesis occur simultaneously following a tightly regulated developmental program influenced by growth factors, extracellular matrix components and cell membrane receptors. Both processes of angiogenesis and vasculogenesis probably participate in the formation of renal vessels. The origin and fate of the various renal vascular cells and the molecular mechanisms that initiate and guide intrarenal vascularization are fundamental questions that remain to be answered.

Animals↗
PubMed1995

The epidermis is a source of directional information for the migrating pronephric duct in Ambystoma mexicanum embryos.

In the urodele Ambystoma mexicanum, the pronephric duct (PND) is formed from a coherent group of cells that migrate from the pronephros to the cloaca along a pathway immediately ventral to the developing somites. The guidance cues used by the migrating PND primordium to find the cloaca are a local property of the migration substratum, are temporally regulated, and are both polarized and oriented. Since the pronephric duct migrates between two tissues--the underlying lateral mesoderm and the overlying epidermis--we performed a study to identify the tissue(s) in which PND guidance cues originate. Through direct manipulation of the epidermis overlying the duct pathway, we show that the migrating PND reads epidermally derived cues (1) along the anterior-posterior axis that direct migration from anterior to posterior and (2) along the dorsal-ventral axis that constrain migration to the duct pathway. Heterochronic grafting experiments reveal that the ability to direct PND migration is a stable property of flank epidermis throughout the period of PND migration. Epidermal cues are, therefore, not responsible for the observed temporal restrictions on PND migration. Thus, the region of the embryo within which the advancing PND tip can migrate actually represents an area where two distinct but required sets of PND migration cues overlap. The epidermis overlying the duct pathway provides directional information; temporal restriction of duct migration is hypothesized to be a property of the flank mesoderm.

Ambystoma mexicanum↗
PubMed2002

Differential effects of DNA tumor virus genes on the expression profiles, differentiation, and morphogenetic reprogramming potential of epithelial cells.

The availability of cell lines that retain their differentiation programs is important for the study of differentiated cell types and the development of cell therapies. DNA tumor virus genes are often used to establish cell lines from primary culture for the analysis of cell-specific functions. To ascertain whether viral immortalizing or transforming genes differed in their effects on cellular differentiation programs, the E1A 12S (WT12S) gene of adenovirus and the large T antigen (LT) gene of SV40 were used to derive stable cell lines from primary kidney. The resultant cell types exhibited very different morphologies, growth and behavior patterns, differentiation states, and plasticities. Renal cells immortalized by LT exhibited branching tubulogenesis in response to Matrigel. This was in contrast to their behavior under normal culture conditions, wherein they were less differentiated, very nonadhesive, very rapidly growing, and transformed. These cells coexpressed adult epithelial (keratin) and embryonic mesenchymal (vimentin, osteopontin, FSP1, PAX-2, and WT1) genes. WT12S-immortalized cells grown on or in Matrigel formed cysts or tubules, consistent with their expression profiles, which consisted of both epithelial and adult kidney markers (E-cadherin, alpha-catenin, circumferential actin filaments (CAF), alkaline phosphatase, aminopeptidase M, BMP7, or podocalyxin), but not embryonic/mesenchymal markers (PAX-2 or WT1). The WT12S-expressing cells were well differentiated, adhesive, slow growing, and nontransformed. Thus, cells expressing WT12S maintained their original differentiation status and were less sensitive to reprogramming, while cells expressing LT were dedifferentiated, but had the potential for reprogramming by exogenous factors.

Animals↗
PubMed2001

Renal cell cultures for the study of growth factor interactions underlying kidney organogenesis.

The present study was performed in four renal cell lines to evaluate their capability to: (1) produce and express transforming growth factor alpha (TGFalpha), its respective receptor, the epidermal growth factor receptor (EGFr) and the small G protein, RhoA, and (2) exhibit morphogenetic properties when grown on Matri-cell substrates. The cell lines were derived from normal (Madin-Darby canine kidney cells), embryonic (SK-NEP-1 and 293 cells), and cancerous (human renal adenocarcinoma cells) kidneys. TGFalpha messenger ribonucleic acid, evaluated by a nonradioactive in situ hybridization technique, was found to be expressed in all the cell lines. Large amounts of TGFalpha peptide were observed in all four cell lines, while EGFr was highly expressed only in cancerous ACHN and embryonic-tumor SK-NEP-1 cells. RhoA peptide was found in appreciable amounts in SK-NEP-1 and 293 cells (compared to the other two cell lines). The morphogenetic properties of the four cell lines were assessed, by culturing them on Matri-cell dishes: SK-NEP-1 cells alone were found to grow in three-dimensional structures forming clusters and worm-like cellular aggregates. This feature was displayed by SK-NEP-1 cells but not by the other three cell lines, and may be connected with the contemporary presence of RhoA, EGFr, and TGFalpha found in significant amounts only in the SK-NEP-1 cell line.

Animals↗
PubMed1996

Novel Madin Darby canine kidney cell clones exhibit unique phenotypes in response to morphogens.

Novel Madin Darby Canine Kidney cell clones were isolated. These cell clones exhibit differential responsiveness to inducers of tubule or cyst formation in collagen gel culture: hepatocyte growth factor or inducers of intracellular cAMP formation, respectively. In gel culture, clone OR93.22.D6 forms cysts and responds with morphological transformation to both hepatocyte growth factor and prostaglandin E1, and is most typical of a previously described cell type except for its higher transepithelial electrical resistance. OR55.25.II20 forms tubules in culture, is unresponsive to hepatocyte growth factor, and forms prostaglandin-induced spherical cysts. OR55.28.V2 forms dense cell spheres under control conditions, is induced to form tubules by hepatocyte growth factor, and is unresponsive to prostaglandin. OR55.29 forms only cysts, and is the only clone to form domes in monolayer culture. Tubule formation induced by hepatocyte growth factor, in all clones except OR55.25.II20, is blocked by a neutralizing antibody. In defined medium, without hepatocyte growth factor or prostaglandin, OR55.25.II20 forms spontaneous tubules. This finding indicates that a tubulogenic serum factor is not responsible for the observed phenotype. Increasing prostaglandin concentrations lead to inhibition of tubule formation and increased cyst formation. This observation suggests that induction of intracellular cAMP formation negatively regulates tubule formation in these cells, and implies that cystogenesis may represent a "default pathway" for impaired tubulogenesis. These observations demonstrate that some facets of renal tubulogenesis may be independent of hepatocyte growth factor, and that care must be exercised when comparing biological studies utilizing different clones.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Chemotaxis or adhesion gradient? Pronephric duct elongation does not depend on distant sources of guidance information.

Previously published experimental studies have led to conflicting interpretations concerning the mechanism guiding pronephric duct elongation in the urodele embryo. Although most studies have led to the conclusion that duct migration is directed by an adhesion gradient (haptotaxis), one set of experiments has been interpreted as supporting chemotactic guidance. We have resolved this conflict by conducting grafting experiments in Ambystoma embryos which distinguish between these two possible mechanisms of cell guidance. Our results provide an alternative explanation for the observations originally interpreted as supporting chemotaxis and add further evidence for adhesive guidance.

Ambystoma↗