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PubMed2000

Influence of FGF4 on digit morphogenesis during limb development in the mouse.

Much of what we currently know about digit morphogenesis during limb development is deduced from embryonic studies in the chick. In this study, we used ex utero surgical procedures to study digit morphogenesis during mouse embryogenesis. Our studies reveal some similarities; however, we have found considerable differences in how the chick and the mouse autopods respond to experimentation. First, we are not able to induce ectopic digit formation from interdigital cells as a result of wounding or TGFbeta-1 application in the mouse, in contrast to what is observed in the chick. Second, FGF4, which inhibits the formation of ectopic digits in the chick, induces a digit bifurcation response in the mouse. We demonstrate with cell marking studies that this bifurcation response results from a reorganization of the prechondrogenic tip of the digit rudiment. The FGF4 effect on digit morphogenesis correlates with changes in the expression of a number of genes, including Msx1, Igf2, and the posterior members of the HoxD cluster. In addition, the bifurcation response is digit-specific, being restricted to digit IV. We propose that FGF4 is an endogenous signal essential for skeletal branching morphogenesis in the mouse. This work stresses the existence of major differences between the chick and the mouse in how digit morphogenesis is regulated and is thus consistent with the view that vertebrate digit evolution is a relatively recent event. Finally, we discuss the relationship between the digit IV bifurcation restriction and the placement of the metapterygial axis in the evolution of the tetrapod limb.

Animals↗
PubMed2000

The ERK-1/2 signaling pathway is involved in the stimulation of branching morphogenesis of fetal mouse submandibular glands by EGF.

We have previously reported that epidermal growth factor (EGF) stimulates branching morphogenesis of the fetal mouse submandibular gland (SMG) (M. Kashimata and E. W. Gresik, 1997, Dev. Dyn. 208, 149-161) and that the EGF receptor (EGFR) is localized principally, if not exclusively, on the epithelial components of the fetal SMG (E. W. Gresik, M. Kashimata, Y. Kadoya, R. Mathews, N. Minami, and S. Yamashina, 1997, J. Histochem. Cytochem. 45, 1651-1657). The EGFR is a receptor tyrosine kinase, and after binding of its ligand, it triggers several intracellular signaling cascades, among them the one activating the mitogen-activated protein kinases (MAPK) ERK-1/2. Here we investigated whether EGF utilizes the ERK-1/2 signaling cascade to stimulate branching morphogenesis in the fetal mouse SMG. SMG rudiments were collected as matched pairs at E14, E16, and E18 (E0 = day of vaginal plug); placed into wells of defined medium (BGJb); and exposed to EGF for 5 or 30 min or to medium alone (controls). By Western blotting we found that EGF induced the appearance of multiple bands of phosphotyrosine-containing proteins, including bands at 170 kDa and 44 kDa/42 kDa, presumably corresponding to the phosphorylated forms of EGFR and ERK-1/2, respectively. Other blots showed the specific appearance of the phosphorylated EGFR and of phospho-ERK-1/2 in response to EGF. Immunohistochemical staining for phosphotyrosine increased at the plasma membrane after EGF stimulation for 5 or 30 min. Diffuse cytoplasmic staining for MEK-1/2 (the MAPK kinase that activates ERK-1/2) increased near the cell membrane after EGF stimulation. Phospho-ERK-1/2 was localized in the nuclei of a few epithelial cells after EGF for 5 min, but in the nuclei of many cells after EGF for 30 min. PD98059, an inhibitor of phosphorylation and activation of MEK-1/2, by itself inhibited branching morphogenesis and, furthermore, decreased the stimulatory effect of EGF on branching. Western blots confirmed that this inhibitor blocked phosphorylation of ERK-1/2 in fetal SMGs exposed to EGF. These results show that components of the ERK-1/2 signaling cascade are present in epithelial cells of the fetal SMG, that they are activated by EGF, and that inhibition of this cascade perturbs branching morphogenesis. However, EGF did not cause phosphorylation of two other MAPKs, SAPK/JNK or p38MAPK, in fetal SMGs. These results imply that the ERK-1/2 signaling is responsible, at least in part, for the stimulatory effect of EGF on branching morphogenesis of the fetal mouse SMG.

Animals↗
PubMed1986

The cellular basis of epithelial morphogenesis.

Epithelial tissues are ubiquitous in metazoan organisms, performing many different functions and assuming a variety of shapes. This diversity of form and function is ultimately dependent on the behavior of the cells within the epithelia. For example, it is intercellular adhesion and the control of paracellular permeability by cell junctions that permit epithelia to form barriers and act as selective filters. It is cellular polarity that enables absorptive epithelia to extract materials from a particular side of the sheet; it is the collective contributions of cell proliferation, cellular translocation, and changes in cell shape that sculpt epithelia from simple sheets into folds, pouches and tubes. Clearly, a complete understanding of epithelial morphogenesis is inextricably entwined with questions of cell behavior in general, such as how any cell adheres, moves, and maintains its shape. The study of epithelial systems has lent considerable insight into these problems and should continue to do so, just as examination of the behavior and architecture of nonepithelial cells will undoubtedly clarify many aspects of the cellular events underlying epithelial morphogenesis. Although the action of individual cells ultimately shapes epithelial, coordination of that action is necessary for the development of a coherent tissue. Attention must therefore be given to integrative mechanisms in epithelial morphogenesis. How do the many cells in an epithelial sheet act in virtual unison during folding? What defines the boundaries of epithelial invaginations? How does an individual cell detect its position within, and thereby know its role in the morphogenesis of, the epithelial whole of which it is a part? At the most elementary level, epithelial cells interact via their physical attachments to one other. Even such rudimentary communication affects cell shape, movement, and possibly proliferation and also plays a part in the maintenance of epithelial polarity. Additional signals pass among epithelial cells by a number of other mechanisms as well, most notably electrical coupling. However, many questions remain regarding the quality and quantity of what is communicated between epithelial cells. Accordingly, elucidating the means by which supracellular order is maintained in epithelial tissues may still be regarded as the major problem in the study of epithelial morphogenesis.

Animals↗
PubMed1996

Hepatocyte growth factor in lung morphogenesis and tumor invasion: role as a mediator in epithelium-mesenchyme and tumor-stroma interactions.

Hepatocyte growth factor (HGF), a ligand for Met tyrosine kinase, is a mesenchyme- or stroma-derived multipotent factor that regulates the growth, motility, and morphogenesis of various types of cells. During lung development, Met/HGF receptor mRNA was localized in lung epithelial cells, whereas HGF mRNA was localized in lung mesenchymal cells in rat embryos. Antisense HGF oligonucleotides specifically inhibited epithelial branching morphogenesis in cultured lung rudiment isolated from day-13 rat embryos, whereas recombinant HGF stimulated branching morphogenesis. Thus, HGF seems to be at least one of the mesenchyme-derived factors that support branching morphogenesis during lung development. Together with the finding that HGF plays important roles in organogenesis and morphogenesis of organs such as the liver and kidney, HGF seems to be a mediator in epithelium-mesenchyme interactions during organogenesis. Extending the conceptual framework of epithelium-mesenchyme (or epithelium-stroma) interactions, we next examined the possible involvement of HGF in tumor-stroma interactions, because the growth and motility of carcinoma cells are regulated through their interactions with host stromal cells. HGF induced in vitro migration and invasion of GB-d1 gallbladder carcinoma cells into basement membrane components and collagen-gel matrix; however, several other growth factors did not induce marked migration and invasion of the carcinoma cells. GB-d1 cells do not produce HGF, but they produce in inducing factor for HGF production in fibroblasts; the inducing molecule was identified as interleukin 1 beta. Cocultivation of GB-d1 cells with stromal fibroblasts embedded in a collagen-gel matrix induced invasion of GB-d1 cells into the collagen gels, but invasion was inhibited by a specific antibody against HGF. This indicates that in vitro invasion of GB-d1 cells depends on stromal fibroblasts and that the fibroblast-derived invasion factor is HGF. Since HGF stimulated in vitro migration and invasion of various carcinoma cells and several carcinoma cells produced inducing factors for HGF production in stromal fibroblasts, the looped interaction of carcinoma cells and stromal fibroblasts mediated by HGF and HGF inducers may be a mechanism responsible for acquisition of the malignant phenotype through tumor-stroma interactions.

Animals↗
PubMed2005

The integration of cell proliferation and growth in leaf morphogenesis.

A number of recent publications have assessed the outcome on leaf development of targeted manipulation of cell proliferation. The results of these investigations have awakened interest in the long-standing debate in plant biology on the precise role of cell division in morphogenesis. Does cell proliferation drive morphogenesis (cell theory) or is it subservient to a mechanism which acts at the whole organ level to regulate morphogenesis (organismal theory)? In this review, the central role of growth processes (distinct from cell proliferation) in morphogenesis is highlighted and the limitations in our understanding of the basic mechanisms of plant growth control are highlighted. Finally, an attempt is made to demonstrate how sequential local co-ordination of growth might provide an interpretation of some of the recent observations on cell proliferation and leaf morphogenesis.

Cell Proliferation↗
PubMed1985

Epidermal growth factor inhibits morphogenesis and cell differentiation in cultured mouse embryonic teeth.

Although local epithelial-mesenchymal tissue interactions which are presumably mediated by extracellular matrix molecules are important regulators of tooth morphogenesis and differentiation, our studies have indicated that these developmental processes also depend on circulating molecules. The iron-carrying serum protein transferrin is necessary for the early morphogenesis of mouse tooth in organ culture (A-M. Partanen, I. Thesleff, and P. Ekblom, 1984, Differentiation 27, 59-66). In the present study we have examined the effects of other growth factors on mouse tooth germs grown in a chemically defined medium containing transferrin. Fibroblast growth factor and platelet derived growth factor had no detectable effects but epidermal growth factor (EGF) inhibited dramatically the morphogenesis of teeth, and prevented odontoblast and ameloblast cell differentiation. EGF stimulated cell proliferation in the explants measured as [3H]thymidine incorporation in DNA. However, when the distribution of dividing cells was visualized in autoradiographs, it was observed that cell proliferation was stimulated in the dental epithelium but was inhibited in the dental mesenchyme. The inhibition of cell proliferation in the dental mesenchyme apparently caused the inhibition of morphogenesis. We do not know whether the dental epithelium or mesenchyme was the primary target for the action of EGF in the inhibition of morphogenesis. It is, however, apparent that the response of the dental mesenchymal cells to EGF (inhibition of proliferation) is regulated by their local environment, since EGF enhanced proliferation when these cells were disaggregated and cultured as monolayers. This indicates that the organ culture system where the various embryonic cell lineages are maintained in their original environment corresponds better to the in vivo situation when the roles of exogenous growth factors during development are examined.

Animals↗
PubMed1988

The effect of androgen deprivation on branching morphogenesis in the mouse prostate.

Androgen-induced prostatic development encompasses many individual processes such as ductal branching morphogenesis, cellular proliferation, and secretory cytodifferentiation. Previous studies of ductal morphogenesis (Y. Sugimura, G.R. Cunha, and A.A. Donjacour, 1986, Biol. Reprod. 34, 961-971) demonstrated that the majority (approximately 70%) of ductal tips and branchpoints in the mouse prostate is generated before 15 days of age. Since circulating androgen levels are low during this neonatal period, it is possible that ductal branching morphogenesis may not require the continuous presence of androgens. To test this hypothesis mice were castrated within 24 hr of birth, and prostates from these mice were microdissected at various ages from 5 to 120 days of age to assess the number of ductal tips and branchpoints; wet weight and DNA content were also determined. In intact males wet weight and DNA content increased rapidly between 15 and 60 days of age, after most of the prostatic ductal architecture had been laid down. Neonatal castration considerably reduced the number of tips and branchpoints in both the ventral and dorsolateral prostate, yet both lobes still underwent significant branching morphogenesis in the absence of testes. The administration of anti-androgens to neonatal castrates did not suppress ductal branching to any greater extent than did neonatal castration alone. Androgen replacement immediately following neonatal castration resulted in precocious attainment of the adult number of tips and branchpoints, but caused only modest increases in wet weight. In contrast, when androgen replacement was delayed until adulthood, prostatic wet weight increased to normal adult levels, but the number of ductal tips and branchpoints did not. These experiments show that neonatal prostatic ductal morphogenesis is sensitive to, but does not require, chronic androgen stimulation.

Androgens↗
PubMed2003

Role of PI 3-kinase and PIP3 in submandibular gland branching morphogenesis.

The mouse submandibular gland (SMG) epithelium undergoes extensive morphogenetic branching during embryonic development as the first step in the establishment of its glandular structure. However, the specific signaling pathways required for SMG branching morphogenesis are not well understood. Using E13 mouse SMG organ cultures, we showed that inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), wortmannin and LY294002, substantially inhibited branching morphogenesis in SMG. Branching morphogenesis of epithelial rudiments denuded of mesenchyme was inhibited similarly, indicating that PI 3-kinase inhibitors act directly on the epithelium. Immunostaining and Western analysis demonstrated that the p85 isoform of PI 3-kinase is expressed in epithelium at levels higher than in the mesenchyme. A target of PI 3-kinase, Akt/protein kinase B (PKB), showed decreased phosphorylation at Ser(473) by Western analysis in the presence of PI 3-kinase inhibitors. The major lipid product of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), was added exogenously to SMG via a membrane-transporting carrier in the presence of PI 3-kinase inhibitors and was found to stimulate cleft formation, the first step of branching morphogenesis. Together, these data indicate that PI 3-kinase plays a role in the regulation of epithelial branching morphogenesis in mouse SMG acting through a PIP(3) pathway.

Androstadienes↗
PubMed2000

A novel Akt/PKB-related kinase is essential for morphogenesis in Dictyostelium.

BACKGROUND: Dictyostelium Akt/PKB is homologous to mammalian Akt/PKB and is required for cell polarity and proper chemotaxis during early development. The kinase activity of Akt/PKB kinase is activated in response to chemoattractants in neutrophils and in Dictyostelium by the chemoattractant cAMP functioning via a pathway involving a heterotrimeric G protein and PI3-kinase. Dictyostelium contains several kinases structurally related to Akt/PKB, one of which, PKBR-1, is investigated here for its role in cell polarity, movement and cellular morphogenesis during development. RESULTS: PKBR-1 has a kinase and a carboxy-terminal domain related to those of Akt/PKB, but no PH domain. Instead, it has an amino-terminal myristoylation site, which is required for its constitutive membrane localization. Like Akt/PKB, PKBR-1 is activated by cAMP through a G-protein-dependent pathway, but does not require PI3-kinase, probably because of the constitutive membrane localization of PKBR-1. This is supported by experiments demonstrating the requirement for membrane association for activation and in vivo function of PKBR-1. PKBR-1 protein is found in all cells throughout early development but is then restricted to the apical cells in developing aggregates, which are thought to control morphogenesis. PKBR-1 null cells arrest development at the mound stage and are defective in morphogenesis and multicellular development. These phenotypes are complemented by Akt/PKB, suggesting functional overlap between PKBR-1 and Akt/PKB. Akt/PKB PKBR-1 double knockout cells exhibit growth defects and show stronger chemotaxis and cell-polarity defects than Akt/PKB null cells. CONCLUSIONS: Our results expand the previously known functions of Akt/PKB family members in cell movement and morphogenesis during Dictyostelium multicellular development. The results suggest that Akt/PKB and PKBR-1 have overlapping effectors and biological function: Akt/PKB functions predominantly during aggregation to control cell polarity and chemotaxis, whereas PKBR-1 is required for morphogenesis during multicellular development.

Amino Acid Sequence↗
PubMed1997

The effects of hexetidine (Oraldene) on the adherence of Candida albicans to human buccal epithelial cells in vitro and ex vivo and on in vitro morphogenesis.

PURPOSE: This study reports the effects of hexetidine (Oraldene) on two virulence attributes of Candida albicans, namely, in vitro and ex vivo adherence of yeast cells to buccal epithelial cells (BEC) and in vitro morphogenesis. METHODS: The effects of hexetidine treatment of either yeast cells (stationary and exponential phases) or BEC on Candidal adherence, in terms of viable and non-viable adherent yeast cells, were evaluated using an acridine orange stain in conjunction with fluorescence microscopy. Ex vivo anti-adherence effects were determined by rinsing BEC in vivo with hexetidine (0.1%), removal of BEC after defined periods and inclusion in the adherence assay. The effects of hexetidine on morphogenesis were evaluated using light microscopy. Yeast cell viability following exposure to a range of concentration of hexetidine (0.005-0.1% v/v) for defined periods was determined following serial dilution and enumeration on solid media. RESULTS: Treatment of stationary and exponential phase yeast cells or BEC with hexetidine (0.1%) for a range of times (10-300 s) or, alternatively, with a range of concentrations of hexetidine (0.005-0.1%) for a fixed time (30s) significantly decreased the resultant Candidal/ epithelial adhesion. No correlations were observed between reduced adherence and either time of treatment or hexetidine concentration. In vivo treatment of BEC with hexetidine (0.1%) for 30s resulted in prolonged and significant reductions in the ex vivo adherence of both viable and non-viable yeast cells for periods of up to (and including) four hours post-rinsing. Treatment of C. albicans blastospores with hexetidine (0.05, 0.1% v/v) for 10s and 30s totally inhibited Candida morphogenesis, whereas treatment with lower antiseptic concentrations significantly reduced the extent of Candida morphogenesis and the rate of hyphal development. The effects of hexetidine on yeast cell viability were both concentration and time-dependent. CONCLUSIONS: The reduced adherence of C. albicans to BEC and the modification or inhibition of morphogenesis following exposure to hexetidine suggests a clinical role for hexetidine in the prophylaxis of both superficial candidosis and the systemic complications resulting from invasion of sub-epithelial tissue.

Antifungal Agents↗
PubMed2002

The molecular control of renal branching morphogenesis: current knowledge and emerging insights.

Mammalian kidney development requires the formation of a patterned, branched network of collecting ducts, a process termed renal branching morphogenesis. Disruption of renal branching morphogenesis during human kidney development results in renal dysplasia, the major cause of renal failure in young children. Genetic evidence, combined with in vitro data, have implicated transcription factors, secreted growth factors, and cell surface signaling peptides as critical regulators of renal branching morphogenesis. This review discusses the current knowledge regarding the regulation of renal branching morphogenesis in vivo provided by the analysis of genetic mutations in mice and humans which disrupt collecting duct system development. In addition, in vivo and in vitro evidence regarding the functions of several other gene families are considered, rendering new insight into emerging regulatory roles for these molecules in renal branching morphogenesis.

Animals↗
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↗
PubMed2003

Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase.

Sonic hedgehog (Shh) acts as a morphogen in many cell types. Recent studies have shown that hedgehog signaling is involved in vascular development as well as postnatal angiogenesis. However, the direct action of Shh on cultured endothelial cells has not been clearly shown. To address this issue, we examined the effect of Shh on morphological changes by murine brain capillary endothelial cells (IBE cells) and human umbilical endothelial cells (HUVECs). Shh induced capillary morphogenesis by these cells. The effect was inhibited by cyclopamine or pertussis toxin. Shh-induced capillary morphogenesis was also blocked by LY294002, a phosphoinositide 3-kinase (PI3-kinase) inhibitor. Shh rapidly increased PI3-kinase activity in IBE cells and HUVECs; this activity was inhibited by cyclopamine. Nuclear localization of Gli1 was increased in Shh-treated IBE cells, which was not affected by LY294002. Actinomycin D and cycloheximide inhibited Shh-induced capillary morphogenesis. In IBE cells expressing kinase-inactive c-Fes, Shh failed to stimulate PI3-kinase activity and capillary morphogenesis. Considered collectively, Shh induced capillary morphogenesis of endothelial cells through both rapid activation of c-Fes/PI3-kinase pathways and transcriptionally regulated pathways.

Animals↗
PubMed2005

Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis.

Foxa1 and Foxa2 are closely related family members of the Foxa group of transcription factors that are coexpressed in subsets of respiratory epithelial cells throughout lung morphogenesis. Shared patterns of expression, conservation of DNA binding, and transcriptional activation domains indicate that they may serve complementary functions in the regulation of gene expression during lung morphogenesis. Whereas branching morphogenesis of the fetal lung occurs normally in the Foxa2Delta/Delta and Foxa1-/- mice, deletion of both Foxa1 and Foxa2 (in Foxa2Delta/Delta, Foxa1-/- mice) inhibited cell proliferation, epithelial cell differentiation, and branching. Dilation of terminal lung tubules and decreased branching were observed as early as embryonic day 12.5. Foxa1 and Foxa2 regulated Shh (sonic hedgehog) and Shh-dependent genes in the respiratory epithelial cells that influenced the expression of genes in the pulmonary mesenchyme that are required for branching morphogenesis. Epithelial cell differentiation, as indicated by lack of expression of surfactant protein B, surfactant protein C, the Clara cell secretory protein, and Foxj1, was inhibited. Foxa family members regulate signaling and transcriptional programs required for morphogenesis and cell differentiation during formation of the lung.

Actins↗
PubMed1995

Antibodies against domain E3 of laminin-1 and integrin alpha 6 subunit perturb branching epithelial morphogenesis of submandibular gland, but by different modes.

Branching epithelial morphogenesis requires interactions between the surrounding mesenchyme and the epithelium, as well as interactions between basement membrane components and the epithelium. Embryonic submandibular gland was used to study the roles of two mesenchymal proteins, epimorphin and tenascin-C, as well as the epithelial protein laminin-1 and one of its integrin receptors on branching morphogenesis. Laminin-1 is a heterotrimer composed of an alpha 1 chain and two smaller chains (beta 1 and gamma 1). Immunofluorescence revealed a transient expression of laminin alpha 1 chain in the epithelial basement membrane during early stages of branching morphogenesis. Other laminin-1 chains and alpha 6, beta 1, and beta 4 integrin subunits seemed to be expressed constitutively. Expression of epimorphin, but not tenascin-C, was seen in the mesenchyme during early developmental stages, but a mAb against epimorphin did not perturb branching morphogenesis of this early epithelium. In contrast, inhibition of branching morphogenesis was seen with a mAb against the carboxy terminus of laminin alpha 1 chain, the E3 domain. An inhibition of branching was also seen with a mAb against the integrin alpha 6 subunit. The antibodies against laminin alpha 1 chain and integrin alpha 6 subunit perturbed development in distinct fashions. Whereas treatment with the anti-E3 resulted in discontinuities of the basement membrane at the tips of the branching epithelium, treatment with the mAb against alpha 6 integrin subunit seemed to leave the basement membrane intact. We suggest that the laminin E3 domain is involved in basement membrane formation, whereas alpha 6 beta 1 integrin binding to laminin-1 may elicit differentiation signals to the epithelial cells.

Animals↗
PubMed2006

Cytoskeleton and morphogenesis in brown algae.

BACKGROUND: Morphogenesis on a cellular level includes processes in which cytoskeleton and cell wall expansion are strongly involved. In brown algal zygotes, microtubules (MTs) and actin filaments (AFs) participate in polarity axis fixation, cell division and tip growth. Brown algal vegetative cells lack a cortical MT cytoskeleton, and are characterized by centriole-bearing centrosomes, which function as microtubule organizing centres. SCOPE: Extensive electron microscope and immunofluorescence studies of MT organization in different types of brown algal cells have shown that MTs constitute a major cytoskeletal component, indispensable for cell morphogenesis. Apart from participating in mitosis and cytokinesis, they are also involved in the expression and maintenance of polarity of particular cell types. Disruption of MTs after Nocodazole treatment inhibits cell growth, causing bulging and/or bending of apical cells, thickening of the tip cell wall, and affecting the nuclear positioning. Staining of F-actin using Rhodamine-Phalloidin, revealed a rich network consisting of perinuclear, endoplasmic and cortical AFs. AFs participate in mitosis by the organization of an F-actin spindle and in cytokinesis by an F-actin disc. They are also involved in the maintenance of polarity of apical cells, as well as in lateral branch initiation. The cortical system of AFs was found related to the orientation of cellulose microfibrils (MFs), and therefore to cell wall morphogenesis. This is expressed by the coincidence in the orientation between cortical AFs and the depositing MFs. Treatment with cytochalasin B inhibits mitosis and cytokinesis, as well as tip growth of apical cells, and causes abnormal deposition of MFs. CONCLUSIONS: Both the cytoskeletal elements studied so far, i.e. MTs and AFs are implicated in brown algal cell morphogenesis, expressed in their relationship with cell wall morphogenesis, polarization, spindle organization and cytokinetic mechanism. The novelty is the role of AFs and their possible co-operation with MTs.

Actin Cytoskeleton↗
PubMed2004

Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells.

Interstitial collagen I stimulates microvascular endothelial cells to form solid cords that imitate precapillary structures found during angiogenesis. Time-lapse microscopy identified cell retraction and disruption of cell-cell contacts as early critical steps in collagen I-induced capillary morphogenesis. These early stages paralleled collagen I activation of Src kinase and GTPase Rho through beta1 integrins. The Src inhibitor PP2, dominant-negative Src, and Rho inhibitor exoenzyme C3 transferase each inhibited collagen I induction of actin stress fibers that mediate cell retraction and each inhibited capillary morphogenesis. Collagen I also disrupted VE-cadherin from intercellular junctions through a Src-dependent mechanism; both the Src inhibitor PP2 and dominant-negative Src preserved VE-cadherin localization to regions of cell-cell contact. An active Src mutant disrupted VE-cadherin and cell-cell contacts similarly to collagen I. In sharp contrast, laminin-1 did not induce capillary morphogenesis, and laminin-1 did not induce activation of Src or Rho. Rather, laminin-1 induced persistent activation of the GTPase Rac. Thus, these studies identify activation of Src and Rho as key mechanisms by which collagen I provokes capillary morphogenesis of microvascular endothelial cells, and they define marked differences between the functions of collagen I and laminin-1 in regulating endothelial cell morphogenesis.

ADP Ribose Transferases↗
PubMed2004

A mesenchyme-free culture system to elucidate the mechanism of otic vesicle morphogenesis.

The vertebrate inner ear has been extensively studied as a model system of morphogenesis and differentiation. The interactions between epithelium and surrounding mesenchyme have not previously been studied directly, because an appropriate experimental system had not been established. Here we describe a mesenchyme-free culture system of E11.5 mouse otic vesicle which retains the ability for (1) formation of the cochlear loop, (2) emigration of ganglion cells from the epithelium and (3) invagination of semicircular canal epithelium. E10.5 otic vesicle was maintained using the same method, but morphogenesis was less successful. Culture of the E11.5 cochlear region alone resulted in regeneration of a structure with semicircular canal character from the cut end, indicating that region-specific cell fate within the otic vesicle is not irreversibly determined at this stage. Co-culturing otic vesicle with cochleovestibular ganglion (CVG) resulted in enhanced looping or ectopic diverticulum formation of the cochlear region, suggesting that the CVG provides a morphogenetic signal for cochlear looping. Cochlear looping was specifically blocked by inhibiting actin polymerization by cytochalasin D, while morphogenesis of the semicircular canal region remained intact. Hyaluronidase treatment inhibited semicircular canal morphogenesis, resulting in a cystic form of the otic vesicle. These data validate this culture system as a tool for elucidating the mechanism of morphogenesis of the otic vesicle.

Actins↗