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PubMed1990

The Drosophila IMP-E2 gene encodes an apically secreted protein expressed during imaginal disc morphogenesis.

During metamorphosis, the steroid hormone 20-hydroxyecdysone induces morphogenesis of imaginal discs, including the formation of appendages. IMP-E2 is an ecdysone-dependent, single-copy Drosophila gene, whose transcripts accumulate rapidly in imaginal discs in response to the hormone. The IMP-E2 product is secreted at the apical surface of the disc epithelium in association with disc morphogenesis. The product is also secreted apically by the embryonic ectoderm during mid embryogenesis. The deduced primary structure of the protein reveals the presence of 16, short 3-amino acid repeat motifs (such as EIK and EVK) toward the N-terminal end of the protein, and three long, uncharged domains, containing 43 to 78 residues each, toward the C-terminal end. The predicted structure of the protein suggests that it may participate in multimolecular aggregates. Although the temporal and spatial expression of the IMP-E2 gene are consistent with a role in disc morphogenesis, its specific functions remain to be determined.

Amino Acid Sequence↗

PubMed1991

Prolactin inhibits both thyroid hormone-induced morphogenesis and cell death in cultured amphibian larval tissues.

We describe for the first time the successful organ culture, in a serum-free chemically defined medium, of hind limb buds from stage 54/55 Xenopus laevis tadpoles in which 2 x 10(-9) M triiodothyronine (T3) precociously induces morphogenesis to give rise to morphologically normal limbs within 7 days. It was important to retain the mesenchymal tissue joining the two limb buds in order to obtain limb development in culture. T3 added to tail explants from the same larvae, cultured in parallel with limb buds, induced regression and cell loss at rates comparable to those seen during T3-induced metamorphosis in intact tadpoles. We also demonstrate for the first time that 0.2 units of prolactin (PRL) added at the same time as 2 x 10(-9) M T3 totally blocked both limb development and tail regression over 8 days in culture. When added after T3 had initiated its metamorphic action. PRL arrested further morphogenesis and regression of these two tissues, respectively. Retinoic acid at 10(-7) M had only a marginal effect. Histological examination showed that T3 added to limb buds produced normal chondrogenesis and osteogenesis in vitro as well as skin, muscle, and digit formation, while it produced a rapid and marked histolysis of fin and connective tissue of the tail. The ease of hormonally manipulating both morphogenesis and cell death in culture in opposite directions offers a simple, effective model system for molecular analysis of mechanisms underlying hormone-regulated postembryonic developmental processes.

Animals↗

PubMed1992

Glandular-like morphogenesis of the human submandibular tumor cell line A253 on basement membrane components.

We have studied the interaction of a human tumor cell line, A253, derived from a submandibular gland carcinoma with a differentiation promoting reconstituted basement membrane extract, Matrigel. When cultured on plastic, these cells maintain a flat, cobblestone, epithelial morphology. On Matrigel, A253 cells initially form a honeycomb network of cords of cells which subsequently thickens. With time, these cords of cells become discontinuous and blunted, whereupon multilobular clusters of cells develop. These clusters possess a lumen with polarized, PAS(+) cells containing numerous desmosomes and an abundance of glycogen. Culture of the cells on laminin, the most abundant protein found in Matrigel, also induces this morphologic differentiation. Using synthetic laminin-derived peptides, the biologically active IKVAV-containing site of laminin was most active in attachment assays, as well as in inhibiting glandular-like morphogenesis when added to the media of cells cultured on Matrigel. Antibodies to the cell surface 67- and 32-kDa laminin binding proteins partially inhibited the glandular-like morphogenesis, suggesting that multiple interactions with laminin are likely required for the differentiation process. Our data demonstrate that A253 cells can undergo glandular-like morphogenesis on basement membrane and that laminin appears to be the major initiating factor.

Blotting, Western↗

PubMed1983

Calcium, microfilaments and morphogenesis.

Morphogenesis, the generation of tissue form, is important not only in the embryogenesis of a new individual, but also because a change in morphogenesis may be involved in the establishment of differences between individuals during evolution. Morphogenetic movements are effected in part by coordinated changes in the shapes of individual cells and over the past decade the cellular organelles responsible for cell shape have been identified as microfilaments and microtubules. In non-embryonic systems the contraction of microfilaments is controlled by the level of intracellular free calcium, and so calcium is implicated as an intermediate control mechanism in morphogenisis. Through techniques which perturb the calcium balance of cells, or which measure calcium ion concentration directly, evidence is accumulating that calcium is involved in morphogenetic movements such as gastrulation and neurulation, and related phenomena such as wound healing. Thus fundamental questions about the control of morphogenesis in embryogenesis and evolution may now be couched in more precise terms of the control of intracellular calcium ion balance.

Animals↗

PubMed1988

Embryonic mouse lung morphogenesis and type II cytodifferentiation in serumless, chemically defined medium using prolonged in vitro cultures.

The timing, position and mechanism(s) for determining type II cytodifferentiation during mammalian lung development are not known. To approach this problem, we have cultured Theiler stage 16 embryonic B10.A strain mouse lung primordia (12-days gestation, E12) in serumless, chemically defined medium in the presence or absence of dexamethasone (DEX) for periods up to 27 days in vitro. Morphogenesis and cytodifferentiation were evaluated by light and transmission electron microscopy and immunochemical techniques. Pulmonary surfactant-associated apoproteins (PSAP) were initially expressed by type II cells at 16.5-day gestation in vivo. DEX-supplementation to the culture medium resulted in the accelerated expression of PSAP; the apoprotein isoforms (A1, A2, and A3) produced in vitro were comparable to those synthesized during fetal and postnatal in vivo development by high resolution, two-dimensional gel electrophoresis coupled with immunoblot staining. Cultures without DEX produced PSAP A2 and A3 isoforms, but did not produce A1 (26-31 kDa, pI 5.2-5.3). DEX-treated cultures produced more lamellar bodies within type II cells than non-treated controls. The results demonstrate that long-term cultures of embryonic lung primordia express morphogenesis, cytodifferentiation and the synthesis and secretion of PSAP in the absence of exogenous hormones or growth factors. The data set further supports the hypothesis that morphogenesis and type II cytodifferentiation are regulated by autocrine and paracrine factors intrinsic to the embryonic lung developmental program and independent of exogenous hormone controls.

Adrenal Cortex Hormones↗

PubMed1988

Microtubule cytoskeleton and morphogenesis in the amoebae of the myxomycete Physarum polycephalum.

The amoebae of the myxomycete Physarum polycephalum are of interest in order to analyze the morphogenesis of the microtubule and microfilament cytoskeleton during cell cycle and flagellation. The amoebal interphase microtubule cytoskeleton consists of 2 distinct levels of organization, which correspond to different physiological roles. The first level is composed of the 2 kinetosomes or centrioles and their associated structures. The anterior kinetosomes forming the anterior and posterior flagella are morphologically distinguishable. Each centriole plays a role in the morphogenesis of its associated satellites and specific microtubule arrays. The 2 distinct centrioles correspond to the 2 successive maturation stages of the pro-centrioles which are built during prophase. The second level of organization consists of a prominent microtubule organizing center (mtoc 1) to which the anterior centriole is attached at least during interphase. The mtoc plays a role in the formation of the mitotic pole. These observations based on ultrastructural and physiological analyses of the amoebal cytoskeleton are now being extended to the biochemical level. The complex formed by the 2 centrioles and the mtoc 1 has been purified without modifying the microtubule-nucleating activity of the mtoc 1. Several microtubule-associated proteins have been characterized by their ability to bind taxol-stabilized microtubules. Their functions (e.g., microtubule assembly, protection of microtubules against dilution or cold treatment, phosphorylating and ATPase activities) are under investigation. These biochemical approaches could allow in vitro analysis of the morphogenesis of the amoebal microtubule cytoskeleton.

Cell Differentiation↗

PubMed2004

Hepatitis C virus ultrastructure and morphogenesis.

Details of the ultrastructure of hepatitis C virus (HVC) virion remain unclear because it has proved extremely difficult to visualise virus particles from infected serum and tissues directly. In addition, although much is known about the viral genome, first cloned in 1989, little is known about HCV morphogenesis, due to the lack of an efficient in vitro culture system for HCV propagation. Virus-like particles (VLPs) obtained by expressing genes encoding the HCV structural proteins in mammalian cells can be used as an alternative model for studying HCV morphogenesis. In particular, this HCV-LP model has made it possible to demonstrate that HCV budding occurs at the ER membrane and that the core protein drives this process. The HCV-LP model opens up new possibilities for the investigation of viral morphogenesis and virus-host cell interactions, which may make it possible to establish the long-awaited in vitro culture system for HCV.

Animals↗

PubMed2006

Retention of structural and functional polarity in cultured skate hepatocytes undergoing in vitro morphogenesis.

The present study characterized a primary culture model of hepatocytes isolated from the little skate, Leucoraja erinacea, that maintain remarkable structural and functional polarity over 7 days in culture. Skate hepatocytes were isolated as clusters of 3-20 hepatocytes surrounding a bile canaliculus, rather than as single cells. Trypan blue and propidium iodide exclusion was found to be >98%, and the cells maintained high intracellular concentrations of K+, ATP, and reduced glutathione (GSH), and high ratios of ATP/ADP and GSH/GSSG. Glutathione S-transferase activity remained constant, whereas cytochrome P450 activity declined to 16% of initial levels after 7 days. Quantitative RT-PCR analysis revealed that the mRNA levels of several genes remained constant over the 7-day period, whereas Bsep, the canalicular bile salt export pump, levels declined slowly to 30% of initial values. In the presence of dexamethasone, the cells underwent a morphogenesis in which the clusters reannealed into a three-dimensional network of chords. During this morphogenesis, skate hepatocytes clusters maintained a polarized distribution of actin filaments and microtubules, as well as apical and basolateral membrane domains. Polarity of membrane transport systems was confirmed both morphologically, using antibodies raised against Bsep and Mrp2, the canalicular multispecific organic anion transporter, and functionally, by monitoring secretion of the fluorescent organic anions NBD-taurocholate, a Bsep substrate, and fluorescein-methotrexate, an Mrp2 substrate, into the bile canalicular spaces. Overall, the results indicate that in contrast with mammalian hepatocytes, isolated skate hepatocyte clusters retain polarity in culture, and provide an excellent system for investigating long-term effects of drugs and xenobiotics on hepatobiliary functions, and for studying in vitro morphogenesis.

Animals↗

PubMed2004

Genetic control of cell intercalation during tracheal morphogenesis in Drosophila.

BACKGROUND: Branching morphogenesis transforms an epithelial sheet into a tubular network with distinct features regarding the length and diameter of individual tubes. Branching is controlled by several signaling pathways, but the molecular consequences of these pathways in the responding cells are poorly understood. RESULTS: We have undertaken a detailed characterization of cell rearrangements during tracheal branching morphogenesis in Drosophila embryos with a GFP fusion protein labeling the adherens junctions (AJs) and high-resolution live imaging. To analyze the branching process at the cellular level, we further developed an imaging approach that allows us to follow single cells during the branching process. We find that controlled cell intercalation, which requires extensive AJ remodeling, is key to the formation of tracheal branches of different cellular complexities. In particular, most branches consist of tubes with individual cells wrapped around the lumen. These branches form through cell intercalation, which requires the transformation of most of the initial intercellular AJs into autocellular AJs. We propose a step-wise model explaining how this AJ remodeling occurs and use this model to better understand defects in various mutants. We find that Dpp and Wnt signaling control cell intercalation by regulating the expression of Spalt, a zinc finger transcription factor; Spalt inhibits intercalation, leading to the formation of large, multicellular tubes. CONCLUSION: Tracheal morphogenesis is regulated by an interplay of different signaling systems that control cell migration and cell intercalation, respectively. Only the combined action of these signaling systems allows efficient branch elongation and the formation of morphologically distinct branches.

Adherens Junctions↗

PubMed2005

Preferential adhesion mediated by Hibris and Roughest regulates morphogenesis and patterning in the Drosophila eye.

Cell adhesion is essential for morphogenesis; however, the mechanisms by which cell adhesion coordinates precisely regulated morphogenesis are poorly understood. Here we analyze the morphogenetic processes that organize the interommatidial precursor cells (IPCs) of the Drosophila pupal eye. We demonstrate that the Drosophila immunoglobulin superfamily members Hibris and Roughest are essential for IPC morphogenesis in the eye. The two loci are expressed in complementary cell types, and Hibris and Roughest proteins bind directly in vivo. Primary pigment cells employ Hibris to function as organizers in this process; IPCs minimize contacts with neighboring IPCs and utilize Roughest to maximize contacts with primaries. In addition, we provide evidence that interactions between Hibris and Roughest promote junction formation and that levels of Roughest in individual cells determine their capacity for competition. Our results demonstrate that preferential adhesion mediated by heterophilic interacting cell-adhesion molecules can create a precise pattern by minimizing surface free energy.

Animals↗

PubMed2006

Actin-based forces driving embryonic morphogenesis in Caenorhabditis elegans.

Morphogenesis is the process by which multicellular organisms transform themselves from a ball of cells into an organized animal. Certain virtues of Caenorhabditis elegans make it an excellent model system for the study of this process: it is genetically tractable, develops as a transparent embryo with small cell-numbers, and yet still contains all the major tissues typical of animals. Furthermore, certain morphogenetic events are also amenable to study by direct manipulation of the cells involved. Given these advantages, it has been possible to use C. elegans to investigate the different ways in which the actin cytoskeleton drives the cellular rearrangements underlying morphogenesis, through regulated polymerization or actomyosin contraction. Recent insights from this system have determined the involvement in morphogenesis of key proteins, including the actin-regulating WASP and Ena proteins, potential guidance molecules such as the Eph and Robo receptors, and the cell-cell signaling proteins of the Wnt pathway.

Actins↗

PubMed2006

Morphogenesis and cell cycle progression in Candida albicans.

Candida albicans, an opportunistic human pathogen, displays three modes of growth: yeast, pseudohyphae and true hyphae, all of which differ both in morphology and in aspects of cell cycle progression. In particular, in hyphal cells, polarized growth becomes uncoupled from other cell cycle events. Yeast or pseudohyphae that undergo a cell cycle delay also exhibit polarized growth, independent of cell cycle progression. The Spitzenkörper, an organelle composed of vesicles associated with hyphal tips, directs continuous hyphal elongation in filamentous fungal species and also in C. albicans hyphae. A polarisome mediates cell cycle dependent growth in yeast and pseudohyphae. Regulation of morphogenesis and cell cycle progression is dependent upon specific cyclins, all of which affect morphogenesis and some of which function specifically in yeast or hyphal cells. Future work will probably focus on the cell cycle checkpoints involved in connecting morphogenesis to cell cycle progression.

Candida albicans↗

PubMed2004

Transmembrane/juxtamembrane domain-dependent Dscam distribution and function during mushroom body neuronal morphogenesis.

Besides 19,008 possible ectodomains, Drosophila Dscam contains two alternative transmembrane/juxtamembrane segments, respectively, derived from exon 17.1 and exon 17.2. We wondered whether specific Dscam isoforms mediate formation and segregation of axonal branches in the Drosophila mushroom bodies (MBs). Removal of various subsets of the 12 exon 4s does not affect MB neuronal morphogenesis, while expression of a Dscam transgene only partially rescues Dscam mutant phenotypes. Interestingly, differential rescuing effects are observed between two Dscam transgenes that each possesses one of the two possible exon 17s. Axon bifurcation/segregation abnormalities are better rescued by the exon 17.2-containing transgene, but coexpression of both transgenes is required for rescuing mutant viability. Meanwhile, exon 17.1 targets ectopically expressed Dscam-GFP to dendrites while Dscam[exon 17.2]-GFP is enriched in axons; only Dscam[exon 17.2] affects MB axons. These results suggest that exon 17.1 is minimally involved in axonal morphogenesis and that morphogenesis of MB axons probably involves multiple distinct exon 17.2-containing Dscam isoforms.

Alternative Splicing↗

PubMed2004

A Titin mutation defines roles for circulation in endothelial morphogenesis.

Morphogenesis of the developing vascular network requires coordinated regulation of an extensive array of endothelial cell behaviors. Precisely regulated signaling molecules such as vascular endothelial growth factor (VEGF) direct some of these endothelial behaviors. Newly forming blood vessels also become subjected to novel biomechanical forces upon initiation of cardiac contractions. We report here the identification of a recessive mouse mutation termed shrunken-head (shru) that disrupts function of the Titin gene. Titin was found to be required for the initiation of proper heart contractions as well as for maintaining the correct overall shape and orientation of individual cardiomyocytes. Cardiac dysfunction in shrunken-head mutant embryos provided an opportunity to study the effects of lack of blood circulation on the morphogenesis of endothelial cells. Without blood flow, differentiating endothelial cells display defects in their shapes and patterns of cell-cell contact. These endothelial cells, without exposure to blood circulation, have an abnormal distribution within vasculogenic vessels. Further effects of absent blood flow include abnormal spatial regulation of angiogenesis and elevated VEGF signaling. The shrunken-head mutation has provided an in vivo model to precisely define the roles of circulation on cellular and network aspects of vascular morphogenesis.

Animals↗

PubMed2004

Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis.

Runx2 (Cbfa1) is a runt domain transcription factor that is essential for bone development and tooth morphogenesis. Teeth form as ectodermal appendages and their development is regulated by interactions between the epithelium and mesenchyme. We have shown previously that Runx2 is expressed in the dental mesenchyme and regulated by FGF signals from the epithelium, and that tooth development arrests at late bud stage in Runx2 knockout mice [Development 126 (1999) 2911]. In the present study, we have continued to clarify the role of Runx2 in tooth development and searched for downstream targets of Runx2 by extensive in situ hybridization analysis. The expression of Fgf3 was downregulated in the mesenchyme of Runx2 mutant teeth. FGF-soaked beads failed to induce Fgf3 expression in Runx2 mutant dental mesenchyme whereas in wild-type mesenchyme they induced Fgf3 in all explants indicating a requirement of Runx2 for transduction of FGF signals. Fgf3 was absent also in cultured Runx2-/- calvarial cells and it was induced by overexpression of Runx2. Furthermore, Runx2 was downregulated in Msx1 mutant tooth germs, indicating that it functions in the dental mesenchyme between Msx1 and Fgf3. Shh expression was absent from the epithelial enamel knot in lower molars of Runx2 mutant and reduced in upper molars. However, other enamel knot marker genes were expressed normally in mutant upper molars, while reduced or missing in lower molars. These differences between mutant upper and lower molars may be explained by the substitution of Runx2 function by Runx3, another member of the runt gene family that was upregulated in upper but not lower molars of Runx2 mutants. Shh expression in mutant enamel knots was not rescued by FGFs in vitro, indicating that in addition to Fgf3, Runx2 regulates other mesenchymal genes required for early tooth morphogenesis. Also, exogenous FGF and SHH did not rescue the morphogenesis of Runx2 mutant molars. We conclude that Runx2 mediates the functions of epithelial FGF signals regulating Fgf3 expression in the dental mesenchyme and that Fgf3 may be a direct target gene of Runx2.

Animals↗

PubMed2005

Autocrine EGF receptor activation mediates endothelial cell migration and vascular morphogenesis induced by VEGF under interstitial flow.

We show here that autocrine ligand activation of epidermal growth factor (EGF) receptor in combination with interstitial flow is critically involved in the morphogenetic response of endothelial cells to VEGF stimulation. Human umbilical vein endothelial cell (HUVEC) monolayers cultured on a collagen gel and exposed to low interstitial flow in the absence of EGF and VEGF remained viable and mitotic but exhibited little evidence of vascular morphogenesis. Addition of VEGF produced a flow-dependent morphogenetic response within 48 to 72 h, characterized by branched capillary-like structures. The response was substantially abolished by inhibitors related to the autocrine EGF receptor pathway including Galardin, AG1478, PD98059, and an EGF receptor-blocking antibody, indicating that regulation of the morphogenetic process operates via autocrine EGF receptor activation. Moreover, we observed that in our system the EGF receptor was always activated independently of the interstitial flow, and, in addition, the EGF receptor inhibitors used above reduced the phosphorylation state of the receptor, correlating with inhibition of capillary morphogenesis. Finally, 5'bromo-2'-deoxyuridine (BrdU) labeling identified dividing cells at the monolayer but not in the extending capillary-like structures. EGF pathway inhibitors Galardin and AG1478 did not reduce BrdU incorporation in the monolayer, indicating that the EGF-receptor-mediated morphogenetic behavior is mainly due to cell migration rather than proliferation. Based on these results, we propose a two-step model for in vitro capillary morphogenesis in response to VEGF stimulation with interstitial fluid flow: monolayer maintenance by mitotic activity independent of EGF receptors and a migratory response mediated by autocrine EGF receptor activation wherein cells establish capillary-like structures.

Autocrine Communication↗

PubMed2026

Mechanistic analysis of rice caryopsis morphogenesis regulated by exogenous hormones and related precursor substances under blue light conditions.

Rice caryopsis morphogenesis is regulated by light signals and hormonal networks. However, the mechanism by which exogenous hormones and related precursor substances modulate rice caryopsis morphogenesis under blue light remains elusive. In the present study, we aimed to elucidate the molecular mechanisms underlying the regulatory effects of exogenous phytohormones and related precursor substances on caryopsis development at 10 days after pollination (10 DAP) in the japonica rice cultivar 'Chujing 27' under blue light conditions. Results showed that tryptamine treatment increased caryopsis cell volume, thereby significantly driving caryopsis expansion; meanwhile, it markedly enhanced the activities of TDC and TAA, the key rate-limiting enzymes mediating the conversion of tryptophan to auxin, leading to a significant elevation in endogenous auxin content (P < 0.05). In comparison, exogenous auxin treatment significantly boosted carbohydrate accumulation and the activities of associated metabolic enzymes (P < 0.05). Integrated transcriptomic and metabolomic analyses revealed that tryptamine treatment led to significant enrichment of the starch and sucrose metabolic pathway, and drove the coordinated enhancement of carbon metabolic flux and auxin biosynthesis by upregulating key auxin biosynthetic genes (e.g., TAA1) and repressing auxin oxidative degradation. Genes Os04g0531100, Os03g0266100 and Os11g0221200 identified by weighted gene co-expression network analysis (WGCNA) may serve as important candidate targets regulating rice caryopsis morphology and physiological traits under blue light conditions. This study first uncovers the critical function of the "tryptamine-auxin axis" in regulating rice caryopsis development under blue light, laying a theoretical foundation for regulating caryopsis morphogenesis via exogenous hormones and their precursors.

Oryza↗

PubMed2003

Essential embryonic roles of the CKI-1 cyclin-dependent kinase inhibitor in cell-cycle exit and morphogenesis in C elegans.

Following a phase of rapid proliferation, cells in developing embryos must decide when to cease division and then whether to survive and differentiate or instead undergo programmed death. In screens for genes that regulate embryonic patterning of the endoderm in Caenorhabditis elegans, we identified overlapping chromosomal deletions that define a gene required for these decisions. These deletions result in embryonic hyperplasia in multiple somatic tissues, excessive numbers of cell corpses, and profound defects in morphogenesis and differentiation. However, cell-cycle arrest of the germline is unaffected. Cell lineage analysis of these mutants revealed that cells that normally stop dividing earlier than their close relatives instead undergo an extra round of division. These deletions define a genomic region that includes cki-1 and cki-2, adjacent genes encoding members of the Cip/Kip family of cyclin-dependent kinase inhibitors. cki-1 alone can rescue the cell proliferation, programmed cell death, and differentiation and morphogenesis defects observed in these mutants. In contrast, cki-2 is not capable of significantly rescuing these phenotypes. RNA interference of cki-1 leads to embryonic lethality with phenotypes similar to, or more severe than, the deletion mutants. cki-1 and -2 gene reporters show distinct expression patterns; while both are expressed at around the time that embryonic cells exit the cell cycle, cki-2 also shows marked expression starting early in embryogenesis, when rapid cell division occurs. Our findings demonstrate that cki-1 activity plays an essential role in embryonic cell cycle arrest, differentiation and morphogenesis, and suggest that it may be required to suppress programmed cell death or engulfment of cell corpses.

Animals↗