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Results for “Morphogenesis”

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PubMed1998

Roles of hepatocyte growth factor/scatter factor and transforming growth factor-beta1 in mammary gland ductal morphogenesis.

Epithelial-mesenchymal interactions are responsible for the unique pattern of ductal branching morphogenesis characteristic of the mammary gland. To investigate the factors which control the elongation and branching of lactiferous ducts, we developed an in vitro model of ductal morphogenesis in which clonal mouse mammary epithelial cells (TAC-2 cells) are grown in collagen gels. In this experimental system, fibroblast conditioned medium (CM)3 stimulates the formation of extensively arborized tubules. The molecule responsible for this tubulogenic effect was identified as hepatocyte growth factor/scatter factor (HGF/SF). To determine whether HGF/SF plays a role in mammary gland morphogenesis in vivo, the expression of HGF/SF and its receptor, c-Met, were analyzed in the rat mammary gland during pregnancy, lactation, and involution. Levels of HGF/SF and c-Met transcripts were progressively reduced during pregnancy, were virtually undetectable during lactation, and increased again during involution. Collectively, these in vitro and in vivo findings suggest that HGF/SF is a paracrine mediator of mammary gland ductal morphogenesis. We subsequently investigated the effect of another multifunctional cytokine, namely TGF-beta1, on branching morphogenesis of TAC-2 cells. TGF-beta1 had a striking biphasic effect: whereas relatively high concentrations of this cytokine inhibited colony formation, lower concentrations stimulated extensive elongation and branching of epithelial cords. Taken together, these studies indicate that HGF/SF is a stromal-derived paracrine mediator of mammary ductal morphogenesis, and that when present at low concentrations, TGF-beta1 can contribute to this process.

Animals↗

PubMed2004

Neuregulin-1 induces branching morphogenesis in the developing lung through a P13K signal pathway.

Neuregulin-1 (NRG-1) induces signal transduction through the activation of its receptor, a heterodimer of human epidermal growth factor receptors 2 and 3 (HER2/HER3). Signal transduction through this receptor/ligand system plays a critical role in the developing heart, mammary gland, and nervous systems. Previous studies showed that NRG-1-induced HER2 activation resulted in pulmonary epithelial cell proliferation in the human fetal lung. The authors hypothesized that NRG-1 further contributes to lung development and maturation by inducing branching morphogenesis. In the present study, the authors show that NRG-1, HER2, and HER3, but not HER4, are expressed in the developing mouse lung. Addition of NRG-1 to fetal lung explants increased lung branching morphogenesis by 32% (P < .05). This increase in branching was blocked by 2C4, an antibody directed against HER2 that inhibits its dimerization and subsequent NRG-1-induced signal transduction. To gain an understanding of the intracellular signaling pathways involved in NRG-1-induced branching morphogenesis, the authors specifically blocked the phosphatidylinositol-3 kinase (PI3K) and mitogen activation protein kinase (MAPK) pathways. Inhibition of PI3K signaling significantly decreased NRG-1-induced branching morphogenesis (P < .05). Inhibition of NRG-1-induced MAPK activation had no effect on explant branching morphogenesis. These data suggest that NRG-1, binding to the HER2/HER3 heterodimer receptor complex, induces pulmonary branching morphogenesis through HER2 activation of the PI3K pathway.

Animals↗

PubMed1997

Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis.

The characteristic shapes and positions of each individual body muscle are established during the process of muscle morphogenesis in response to patterning information from the surrounding mesenchyme. Throughout muscle morphogenesis, primary myotubes are arranged in small parallel bundles, each myotube spanning the forming muscles from end to end. This unique arrangement potentially assigns a crucial role to primary myotube end regions for muscle morphogenesis. We have cloned muscle ankyrin repeat protein (MARP) as a gene induced in adult rat skeletal muscle by denervation. MARP is the rodent homologue of human C-193 (Chu, W., D.K. Burns, R.A. Swerick, and D.H. Presky. 1995. J. Biol. Chem. 270:10236-10245) and is identical to rat cardiac ankyrin repeat protein. (Zou, Y., S. Evans, J. Chen, H.-C. Kuo, R.P. Harvey, and K.R. Chien. 1997. Development. 124:793-804). In denervated muscle fibers, MARP transcript accumulated in a unique perisynaptic pattern. MARP was also expressed in large blood vessels and in cardiac muscle, where it was further induced by cardiac hypertrophy. During embryonic development, MARP was expressed in forming skeletal muscle. In situ hybridization analysis in mouse embryos revealed that MARP transcript exclusively accumulates at the end regions of primary myotubes during muscle morphogenesis. This closely coincided with the expression of thrombospondin-4 in adjacent prospective tendon mesenchyme, suggesting that these two compartments may constitute a functional unit involved in muscle morphogenesis. Transfection experiments established that MARP protein accumulates in the nucleus and that the levels of both MARP mRNA and protein are controlled by rapid degradation mechanisms characteristic of regulatory early response genes. The results establish the existence of novel regulatory muscle fiber subcompartments associated with muscle morphogenesis and denervation and suggest that MARP may be a crucial nuclear cofactor in local signaling pathways from prospective tendon mesenchyme to forming muscle and from activated muscle interstitial cells to denervated muscle fibers.

Amino Acid Sequence↗

PubMed1972

Dependence of salivary epithelial morphology and branching morphogenesis upon acid mucopolysaccharide-protein (proteoglycan) at the epithelial surface.

The morphogenetic role of the acid mucopolysaccharide (glycosaminoglycan) at the epithelial surface of mouse embryo submandibular glands has been studied by comparing the in vitro morphogenesis of epithelia from which the mucopolysaccharide was removed with that of those that retained the mucopolysaccharide. Epithelia isolated free of mesenchyme by procedures which retain the bulk of surface mucopolysaccharide maintain their lobular shape and undergo uninterrupted branching morphogenesis in culture in direct combination with fresh mesenchyme. Under identical culture conditions, epithelia from which surface mucopolysaccharide was removed lose their lobules and become spherical masses of tissue. During continued culture, the spherical epithelia produce outgrowths from which branching morphogenesis resumes. The morphogenetically active mucopolysaccharide is localized within the basal lamina of the epithelial basement membrane and appears to be bound to protein. During culture in combination with mesenchyme, epithelia undergoing uninterrupted morphogenesis show maximal accumulation of newly synthesized surface mucopolysaccharide at the distal ends of the lobules, the sites of incipient branching. In contrast, the material accumulates nearly equivalently over the surface of the spherical epithelia, with the exception that there is greater accumulation of the material at the surfaces of the budding outgrowths, the sites where morphogenesis will resume. Rapidly proliferating cells are localized within the lobules of epithelia undergoing uninterrupted morphogenesis, but are distributed uniformly in the cortex of the spherical epithelia, except for the outgrowths which show a greater localization of proliferating cells. It is concluded that normal salivary epithelial morphology and branching morphegenesis require the presence of acid mucopolysaccharide-protein within the epithelial basal lamina.

Ammonia↗

PubMed2000

Morphogenesis and tissue engineering of bone and cartilage: inductive signals, stem cells, and biomimetic biomaterials.

Morphogenesis is the developmental cascade of pattern formation, body plan establishment, and the architecture of mirror-image bilateral symmetry of many structures and asymmetry of some, culminating in the adult form. Tissue engineering is the emerging discipline of design and construction of spare parts for the human body to restore function based on principles of molecular developmental biology and morphogenesis governed by bioengineering. The three key ingredients for both morphogenesis and tissue engineering are inductive signals, responding stem cells, and the extracellular matrix. Among the many tissues in the human body, bone has considerable powers for regeneration and is a prototype model for tissue engineering based on morphogenesis. Implantation of demineralized bone matrix into subcutaneous sites results in local bone induction. This model mimics sequential limb morphogenesis and permitted the isolation of bone morphogens. Although it is traditional to study morphogenetic signals in embryos, bone morphogenetic proteins (BMPs), the inductive signals for bone, were isolated from demineralized bone matrix from adults. BMPs and related cartilage-derived morphogenetic proteins (CDMPs) initiate, promote, and maintain chondrogenesis and osteogenesis and have actions beyond bone. The symbiosis of bone inductive and conductive strategies are critical for tissue engineering, and is in turn governed by the context and biomechanics. The context is the microenvironment, consisting of extracellular matrix, which can be duplicated by biomimetic biomaterials such as collagens, hydroxyapatite, proteoglycans, and cell adhesion proteins including fibronectins. Thus, the rules of architecture for tissue engineering are an imitation of the laws of developmental biology and morphogenesis, and thus may be universal for all tissues, including bones and joints.

Adult↗

PubMed1962

Nutrition, growth, and morphogenesis of Mucor rouxii.

Bartnicki-Garcia, S. (Rutgers, The State University, New Brunswick, N.J.) and Walter J. Nickerson. Nutrition, growth, and morphogenesis of Mucor rouxii. J. Bacteriol. 84:841-858. 1962.-Mucor rouxii was grown under three different atmospheres of incubation: air, N(2), and CO(2) in parallel cultures. The atmosphere of incubation markedly affected nutritional requirements, growth, and morphogenesis. Absence of oxygen greatly reduced growth and increased the nutritional demands of the fungus. Presence of a high tension of CO(2) resulted in a change from filamentous to yeastlike morphogenesis. Aerobically, a large variety of carbon sources was utilized; anaerobically, only hexoses served to meet requirements for carbon and energy. Aerobically, various amino acids supported abundant growth; anaerobically, they were poorly utilized. Ammonium and nitrate ions were better sources of nitrogen for anaerobic growth. In general, incubation under either air or N(2) resulted in development of coenocytic filamentous mycelium, whereas incubation under CO(2) resulted in development of budding yeastlike cells. Variations in temperature and time of incubation, inoculum size, type and concentration of carbon source, type of nitrogen source, and presence of various substances with known action on fungal morphogenesis altered growth in many cases, but did not significantly affect the patterns of vegetative morphogenesis conditioned by each atmosphere of incubation. However, vegetative morphogenesis was strongly affected by addition of certain chelating agents. Yeastlike development of M. rouxii was prevented by ethylene-diaminetetraacetic acid (EDTA) in concentrations which were also partially inhibitory for growth; under these conditions, development was filamentous. Chemically related chelating agents were similarly active. The growth-inhibitory and morphogenetic effects of EDTA were reversed by transition-group metal ions. Yeastlike development of M. subtilissimus, which does not require CO(2) for its induction, was also inhibited by EDTA.

Amino Acids↗

PubMed2002

Embryonic submandibular gland morphogenesis: stage-specific protein localization of FGFs, BMPs, Pax6 and Pax9 in normal mice and abnormal SMG phenotypes in FgfR2-IIIc(+/Delta), BMP7(-/-) and Pax6(-/-) mice.

Embryonic submandibular salivary gland (SMG) initiation and branching morphogenesis are dependent on cell-cell communications between and within epithelium and mesenchyme. Such communications are typically mediated in other organs (teeth, lung, lacrimal glands) by growth factors in such a way as to translate autocrine, juxtacrine and paracrine signals into specific gene responses regulating cell division and histodifferentiation. Using Wnt1-Cre/R26R transgenic mice, we demonstrate that embryonic SMG mesenchyme is derived exclusively from cranial neural crest. This origin contrasts to that known for tooth mesenchyme, previously shown to be derived from both neural crest and nonneural crest cells. Thus, although both SMGs and teeth are mandibular derivatives, we can expect overlap and differences in the details of their early inductive interactions. In addition, since embryonic SMG branching morphogenesis is analogous to that seen in other branching organs, we also expect similarities of expression regarding those molecules known to be ubiquitous regulators of morphogenesis. In this study, we performed an analysis of the distribution of specific fibroblast growth factors (FGFs), FGF receptors, bone morphogenetic proteins (BMPs) and Pax transcription factors, previously shown to be important for tooth development and/or branching morphogenesis, from the time of initiation of embryonic SMG development until early branching morphogenesis. In addition, we report abnormal SMG phenotypes in FgfR2- IIIc(+/Delta), BMP7(-/-) and Pax6(-/-) mice. Our results, in comparison with functional studies in other systems, suggest that FGF-2/FGFR-1, FGF-8/FGFR-2(IIIc) and FGF-10/FGFR-2(IIIb) signaling have different paracrine and juxtacrine functions during SMG initial bud formation and branching. Finally, our observations of abnormal SMGs in BMP7(-/-) and Pax6(-/-) indicate that both BMP7 and Pax6 play important roles during embryonic SMG branching morphogenesis.

Animals↗

PubMed2000

Dihydrotestosterone stimulates branching morphogenesis, cell proliferation, and programmed cell death in mouse embryonic lung explants.

Early gestation lung development is characterized by branching morphogenesis of the airways and basic lung structure formation. Androgens delay late-gestation lung development if the androgen exposure begins in early gestation. We hypothesized that there would be effects of early gestation androgens on lung development. Embryonic mouse lungs (d 11.5) were cultured with dihydrotestosterone (DHT), DHT plus flutamide, or with nothing as controls. Branching morphogenesis was significantly increased after 24, 48, and 72 h of culture. This effect was blocked by simultaneous flutamide treatment. Fetal sex did not influence the DHT response. DHT increased cell proliferation as measured by [3H]thymidine incorporation into DNA. Autoradiography showed prominent [3H]thymidine labeling of epithelia and mesenchyme in regions of new bud formation. DHT treatment significantly increased the thymidine-labeling index of fibroblasts and airway epithelial cells. Programmed cell death, which is found in developing organs in association with cell proliferation during structure formation and tissue remodeling, was studied using terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling assay. In control lungs, programmed cell death occurred in the peripheral mesenchyme surrounding newly forming buds and underlying airway branch points. DHT treatment increased programmed cell death in association with increased branching morphogenesis. Evaluation of near-adjacent sections (control and DHT-treated lungs) showed that apoptotic mesenchymal cells were flanked by [3H]thymidine-labeled fibroblasts and epithelial cells, suggesting a coordination of these processes in the progression of branching morphogenesis. We conclude that androgen enhances the process of early lung morphogenesis by increasing cell proliferation and programmed cell death and by promoting the structural progression of branching morphogenesis.

Animals↗

PubMed2003

Genetic regulation of branching morphogenesis: lessons learned from loss-of-function phenotypes.

Branching morphogenesis, defined as growth and branching of epithelial tubules during embryogenesis, is a fundamental feature of renal, lung, mammary gland, submandibular gland, and pancreatic morphogenesis in mammals. Disruption of branching morphogenesis has been demonstrated to result in maldevelopment of some of these organs. Genetic studies performed in affected humans and mutant mice have implicated transcription factors, secreted growth factors, and cell surface signaling molecules as critical regulators of branching morphogenesis. These factors function within networks that appear to exert tight control over the number and location of branches. This review summarizes current knowledge regarding the molecular control of branching morphogenesis in vivo with particular emphasis on the genetic contribution to perturbed branching morphogenesis in mice and humans.

Animals↗

PubMed1987

A new model system for studying androgen-induced growth and morphogenesis in vitro: the bulbourethral gland.

An organ culture system was devised for neonatal mouse bulbourethral glands (BUGs) in which androgen-dependent development parallels that in vivo. BUGs from 0-day-old (day of birth) mice were grown on Millipore filters placed on metal grids in petri dishes for 3 or 6 days in Dulbecco's Modified Eagle's Medium-Ham's F-12 medium (1:1) containing 10% fetal bovine serum. In medium supplemented with testosterone (T; 10(-7) or 10(-8) M), growth and epithelial morphogenesis of the cultured BUGs were comparable to those of the gland in situ. At lower doses of T (10(-9) -10(-12) M), BUGs showed dose-dependent decreases in the rate of growth and degree of epithelial morphogenesis. BUGs cultured without T contained only 38% as much DNA as those in T-supplemented medium, and epithelial morphogenesis did not occur. Thus, BUG development in vitro was dependent on androgens. The continued, albeit reduced, growth in cultures without T indicates that growth is also partially independent of androgens, but epithelial branching morphogenesis is totally dependent on this hormone. Growth and epithelial morphogenesis were reinitiated in glands that had developed in the absence of T, either in vivo or in vitro, by culturing the BUGs for 3 days in T-containing medium. The growth of BUGs in a serum-free medium with or without T paralleled that in comparable serum-containing cultures in vitro and in normal and castrated animals in situ. Coincubation of BUGs with T and 390 MSD (17 beta-N,N-diisopropylcarbamoyl-4-aza-5 alpha-androstan-3-one), an inhibitor of the enzyme 5 alpha-reductase, resulted in retarded development, indicating that T must be converted to 5 alpha-dihydrotestosterone (DHT) to promote normal BUG growth. Additionally, DHT (10(-8) M) alone could substitute for T in promoting BUG development. Thus, DHT must be the proximal androgen for BUG growth. The BUG is an excellent model system for examining androgen-dependent development and should be useful for studying epithelial morphogenesis, growth, and hormonal effects in vitro.

Androgen Antagonists↗

PubMed1991

Branching morphogenesis of mouse salivary epithelium in basement membrane-like substratum separated from mesenchyme by the membrane filter.

Branching morphogenesis of mouse salivary gland has been studied with organ-culture system. We developed a novel transfilter culture system for analyzing branching morphogenesis of the salivary epithelium. The submandibular salivary epithelium from early 13-day mouse fetus, clotted with Matrigel and separated from the mesenchyme by membrane filter, showed extensive growth and branching morphogenesis, morphological differentiation of lobules and stalks, and a typical cleft shape. The epithelium showed little growth and no branching without Matrigel clot or without the mesenchyme. This branching morphogenesis was induced even when the pore size of the filter was reduced to 0.05 microns. Use of type I collagen gel instead of Matrigel mostly induced incomplete morphogenesis with various histological abnormalities. These results suggest that the salivary epithelium can undergo branching morphogenesis in the absence of the mechanical action of mesenchymal cells although it needs an appropriate extracellular matrix and some mesenchymal factors transmitted through the filter.

Animals↗

PubMed2001

Identification of pleiotrophin as a mesenchymal factor involved in ureteric bud branching morphogenesis.

Branching morphogenesis is central to epithelial organogenesis. In the developing kidney, the epithelial ureteric bud invades the metanephric mesenchyme, which directs the ureteric bud to undergo repeated branching. A soluble factor(s) in the conditioned medium of a metanephric mesenchyme cell line is essential for multiple branching morphogenesis of the isolated ureteric bud. The identity of this factor had proved elusive, but it appeared distinct from factors such as HGF and EGF receptor ligands that have been previously implicated in branching morphogenesis of mature epithelial cell lines. Using sequential column chromatography, we have now purified to apparent homogeneity an 18 kDa protein, pleiotrophin, from the conditioned medium of a metanephric mesenchyme cell line that induces isolated ureteric bud branching morphogenesis in the presence of glial cell-derived neurotrophic factor. Pleiotrophin alone was also found to induce the formation of branching tubules in an immortalized ureteric bud cell line cultured three-dimensionally in an extracellular matrix gel. Consistent with an important role in ureteric bud morphogenesis during kidney development, pleiotrophin was found to localize to the basement membrane of the developing ureteric bud in the embryonic kidney. We suggest that pleiotrophin could act as a key mesenchymally derived factor regulating branching morphogenesis of the ureteric bud and perhaps other embryonic epithelial structures.

Animals↗

PubMed1994

Branching morphogenesis of human mammary epithelial cells in collagen gels.

To study the morphogenesis of human epithelial cells in vitro we have used a three-dimensional collagen matrix and a newly developed mammary epithelial cell line, 1-7 HB2. In standard medium 1-7 HB2 cells formed compact balls/spheres inside collagen type I gels, while cocultivation with various fibroblast cell lines or growth in fibroblast-conditioned media resulted in the appearance of branching structures. At least two different soluble factors secreted by fibroblasts were found to be implicated in the branching morphogenesis. Firstly, hepatocyte growth factor/scatter factor could induce branching in a concentration-dependent manner. Moreover, a polyclonal serum against hepatocyte growth factor/scatter factor completely inhibited the branching morphogenesis induced by medium conditioned by MRC-5 fibroblast cells. In contrast, a morphogenetic activity secreted by human foreskin fibroblasts was identified that appears to be different from hepatocyte growth factor/scatter factor and from a number of other well-characterized growth factors or cytokines. This model system has been used to examine the role of integrins in mammary morphogenesis. The expression of the alpha 2 beta 1, alpha 3 beta 1 and alpha 6 beta 4 integrins was decreased when cells were plated on collagen gels. The addition of specific blocking monoclonal antibodies directed to the alpha 2- and beta 1-integrin subunits to growth media impaired cell-cell interactions and interfered with the formation of compact structures inside collagen gels, suggesting that the alpha 2 beta 1 integrin can control intercellular adhesion in mammary morphogenesis. In contrast one of the blocking monoclonal antibodies against the alpha 3-integrin subunit (P1B5) mimicked the effect of soluble 'morphogens'. Our results suggest that the modulation of alpha 3 beta 1 activity may represent an important event in the induction of branching morphogenesis of human mammary epithelial cells.

Animals↗

PubMed2004

Caenorhabditis elegans WASP and Ena/VASP proteins play compensatory roles in morphogenesis and neuronal cell migration.

We report here that WASP and Ena/VASP family proteins play overlapping roles in C. elegans morphogenesis and neuronal cell migration. Specifically, these studies demonstrate that UNC-34/Ena plays a role in morphogenesis that is revealed only in the absence of WSP-1 function and that WSP-1 has a role in neuronal cell migration that is revealed only in the absence of UNC-34/Ena activity. To identify additional genes that act in parallel to unc-34/ena during morphogenesis, we performed a screen for synthetic lethals in an unc-34 null mutant background utilizing an RNAi feeding approach. To our knowledge, this is the first reported RNAi-based screen for genetic interactors. As a result of this screen, we identified a second C. elegans WASP family protein, wve-1, that is most homologous to SCAR/WAVE proteins. Animals with impaired wve-1 function display defects in gastrulation, fail to undergo proper morphogenesis, and exhibit defects in neuronal cell migrations and axon outgrowth. Reducing wve-1 levels in either unc-34/ena or wsp-1 mutant backgrounds also leads to a significant enhancement of the gastrulation and morphogenesis defects. Thus, unc-34/ena, wsp-1, and wve-1 play overlapping roles during embryogenesis and unc-34/ena and wsp-1 play overlapping roles in neuronal cell migration. These observations show that WASP and Ena/VASP proteins can compensate for each other in vivo and provide the first demonstration of a role for Ena/VASP proteins in gastrulation and morphogenesis. In addition, our results provide the first example of an in vivo role for WASP family proteins in neuronal cell migrations and cytokinesis in metazoans.

Animals↗

PubMed1992

Effects of retinoids on tooth morphogenesis and cytodifferentiations, in vitro.

The first embryonic lower mouse molar was used as a model system to investigate the effects of two retinoids, retinoic acid (RA) and a synthetic analogue, Ch55, on morphogenesis and cytodifferentiations in vitro. Exogenous retinoids were indispensable for morphogenesis of bud, cap and bell-stage molars in serum-free, chemically-defined, culture media. Transferrin and RA or transferrin and Ch55 acted synergistically in promoting morphogenesis from bud and cap-stage explants. Transferrin, per se, had no morphogenetic effect. Epithelial histogenesis, odontoblast functional differentiation and ameloblast polarization always occurred in RA-depleted explants. Comparison of the distributions of bromodeoxyuridine (BrdU) incorporation between explants cultured in the absence or presence of RA revealed that RA could modify the patterns of cell proliferation in the inner dental epithelium and dental mesenchyme. Inner dental epithelium cell proliferation is regulated by the dental mesenchyme through basement membrane-mediated interactions, and tooth morphogenesis is controlled by the dental mesenchyme. Laminin is a target molecule of retinoid action. Using a monospecific antibody, we immunolocalized laminin and/or structurally-related molecules sharing the laminin B chain in the embryonic dental mesenchyme and in the dental basement membrane and showed that RA could promote the synthesis or secretion of these molecules. Based on previous in situ hybridization data, it was speculated that CRABPs might regulate the effects of RA on embryonic dental cell proliferation. The fact that Ch55, a retinoid which does not bind to CRABPs, is 100 times more potent than RA in promoting tooth morphogenesis in vitro seems to rule out this hypothesis. On the other hand, the stage-specific inhibition of tooth morphogenesis by excess RA is consistent with the hypothesis that CRABPs might protect embryonic tissues against potentially teratogenic concentrations of free retinoids.

Animals↗

PubMed1980

Studies on the possible role of cyclic AMP in limb morphogenesis and differentiation.

Recent studies indicate that one of the major functions of the apical ectodermal ridge (AER) of the embryonic chick limb bud is to maintain mesenchymal cells directly subjacent to it (i.e. cells extending 0.4-0.5 mm from the AER), in a labile, undifferentiated condition, and that when mesenchymal cells are freed from the AER's influence either artificially or as a result of normal polarized proximal to distal limb outgrowth, they are freed to commence cyto-differentiation. In a preliminary attempt to investigate at a molecular level the mechanism by which the AER events its 'negative' effect on the cytodifferentiation of subjacent mesenchymal cells, we have examined the effect of a variety of agents that elevate cyclic AMP levels on the morphogenesis and differentiation of the unspecialized subridge mesoderm in an organ culture system. In vitro in the presence of the AER, undifferentiated subridge mesoderm explants undergo remarkably normal morphogenesis characterized primarily by progressive polarized proximal to distal outgrowth and changes in the contour of the developing explant. In the presence of cyclic AMP derivatives, explants fail to undergo the polarized outgrowth and contour changes characteristic of control explants. In fact, in the presence of dibutyrl-cyclic AMP and theophylline, AER-directed morphogenesis essentially ceases during the first day of culture. The cessation of AER-directed morphogenesis in the presence of cyclic AMP derivatives is accompanied by the histochemically and biochemically detectable precocious chondrogenic differentiation of the subridge mesenchymal cells. In control explants, cartilage differentiation only occurs in those proximal cells of the explant which gradually become located greater than 0.4-0.5 mm from the AER. In contrast, in the presence of cyclic AMP derivatives, cartilage differentiation by cells within 0.4-0.5 mm of the AER is detectable from the first day of culture, and by the third day cartilage formation has occurred throughout the entire explant. Overall, these results indicate that elevating the cyclic AMP content of the subridge mesenchymal cells enables the cells to overcome negative influences on cytodifferentiation and the positive influences on morphogenesis being imposed upon them by the AER. On the basis of this observation and previous studies, a testable model on the role of cyclic AMP in limp morphogenesis and differentiation is proposed.

Animals↗

PubMed1983

[Morphogenesis of the lung bud from albino Swiss mice embryos, in organ culture in the presence of anti-lung serum].

The study of morphological figures and morphometrical data observed in lung buds from ETAS, cultured in Agar and OPEP medium, with or without SCAPEP, at different concentrations, in order to detect its influence on the morphogenesis, has shown that: OPEP (5:0) supports gradual morphogenesis for a limited time; OPEP + SCAPEP (5:2) supports gradual morphogenesis for a prolonged time; OPEP+SCAPEP (5:5) supports fast and deep morphogenesis for a short time; OPEP+SCAPEP (5:7,5) causes early inhibition of morphogenesis and survival; SCAPEP (5:0) stops instantly morphogenesis and survival.

Animals↗

PubMed1996

Stimulation and inhibition of human mammary epithelial cell duct morphogenesis in vitro.

We previously determined that normal human mammary epithelial cells (HMECs) placed on the basement membrane-like substance Matrigel form structures, whereas malignant breast cells do not (1). In the present study, we determined that the structures formed by normal cells on Matrigel resembled breast ducts in vivo by electron microscopy, and the process of their formation recapitulated what is known of duct formation in vivo. We therefore used this model to study less well-understood aspects of breast morphogenesis. Two priming signals appeared necessary for initiation of morphogenesis: one provided by the Matrigel and one by the cells in an autocrine fashion. Evidence for this included diminished duct formation by cells plated low-concentration Matrigel or at low cell densities, and the reversal of the latter by conditioned medium from high-density cells on Matrigel. Antibodies to bFGF inhibited morphogenesis, suggesting a stimulatory autocrine role for this factor, and antibodies to TGF-beta 1 stimulated duct formation, suggesting an inhibitory autocrine role. Added TGF-beta 1 abolished morphogenesis and stimulated normal cells to wander through Matrigel as do malignant cells. Conditioned medium from normal cells did not stimulate malignant cells to form ducts, but conditioned medium from tumor cells diminished normal morphogenesis, suggesting that malignant cells secrete an inhibitor of morphogenesis.

Biocompatible Materials↗