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PubMed2004

CompuCell, a multi-model framework for simulation of morphogenesis.

MOTIVATION: CompuCell is a multi-model software framework for simulation of the development of multicellular organisms known as morphogenesis. It models the interaction of the gene regulatory network with generic cellular mechanisms, such as cell adhesion, division, haptotaxis and chemotaxis. A combination of a state automaton with stochastic local rules and a set of differential equations, including subcellular ordinary differential equations and extracellular reaction-diffusion partial differential equations, model gene regulation. This automaton in turn controls the differentiation of the cells, and cell-cell and cell-extracellular matrix interactions that give rise to cell rearrangements and pattern formation, e.g. mesenchymal condensation. The cellular Potts model, a stochastic model that accurately reproduces cell movement and rearrangement, models cell dynamics. All these models couple in a controllable way, resulting in a powerful and flexible computational environment for morphogenesis, which allows for simultaneous incorporation of growth and spatial patterning. RESULTS: We use CompuCell to simulate the formation of the skeletal architecture in the avian limb bud. AVAILABILITY: Binaries and source code for Microsoft Windows, Linux and Solaris are available for download from http://sourceforge.net/projects/compucell/

Animals↗
PubMedDate not supplied

Morphogenesis of callosal arbors in the parietal cortex of hamsters.

The morphogenesis of callosal axons originating in the parietal cortex was studied by anterograde labeling with Phaseolus lectin or biocytin injected in postnatal (P) hamsters aged 7-25 days. Some labeled fibers were serially reconstructed. At P7, some callosal fibers extended as far as the contralateral rhinal fissure, with simple arbors located in the homotopic region of the opposite cortical gray matter, and two or three unbranched sprouts along their trajectory. From P7 to P13, the homotopic arbors became more complex, with branches focused predominantly, but not exclusively, in the supra- and infragranular layers of the homotopic region. Simultaneously, the lateral extension of the trunk axon in the white matter became shorter, finally disappearing by P25. Arbors in the gray matter were either bilaminar (layers 2/3 and 5) or supragranular. A heterotopic projection to the lateral cortex was consistently seen at all ages; the heterotopic arbors follow a similar sequence of events to that seen in homotopic regions. These observations document that callosal axons undergo regressive tangential remodeling during the first postnatal month, as the lateral extension of the trunk fiber gets eliminated. Radially, however, significant arborization occurs in layer-specific locations. The protracted period of morphogenesis suggests a correspondingly long plastic period for this system of cortical fibers.

Animals↗
PubMed1999

The effects of beta-bungarotoxin on the morphogenesis of taste papillae and taste buds in the mouse.

Although it has been long accepted that innervation by a taste nerve is essential for maintenance of taste buds, it is not clear what role, if any, innervation plays in the morphogenesis of taste papillae and taste bud development. The following study was undertaken to determine what effects lack of sensory innervation have on the development of taste papillae and the formation of taste buds in the mouse. Timed-pregnant female mice (n = 3) at gestational day 12 (gd12) were anesthetized and a 1 microl solution (1 microg/microl) of beta-bungarotoxin (beta-BTX), a neurotoxin that disrupts sensory and motor neuron development, was injected into the amniotic cavity of two embryos per dam. Two shams were injected with PBS. Fetuses were harvested at gd18, 1 day before birth, and four beta-BTX-injected embryos, two shams and two controls were fixed in buffered paraformaldehyde. Serial sections were examined for the presence and morphology of taste papillae and taste buds. No nerve profiles were observed in beta-BTX-injected tongues. Although circumvallate papillae were present on beta-BTX tongues, only five fungiform papillae could be identified. Taste buds were present on a large percentage of fungiform papillae profiles (24%) and on circumvallate papillae in sham and control fetuses; in contrast, no taste buds were associated with taste papillae in beta-BTX fetuses. These results implicate a significant role for innervation in taste papillae and taste bud morphogenesis.

Animals↗
PubMed1999

The Rap1 GTPase functions as a regulator of morphogenesis in vivo.

The Ras-related Rap GTPases are highly conserved across diverse species but their normal biological function is not well understood. Initial studies in mammalian cells suggested a role for Rap as a Ras antagonist. More recent experiments indicate functions in calcium- and cAMP-mediated signaling and it has been proposed that protein kinase A-mediated phosphorylation activates Rap in vivo. We show that Ras1-mediated signaling pathways in Drosophila are not influenced by Rap1 levels, suggesting that Ras1 and Rap1 function via distinct pathways. Moreover, a mutation that abolishes the putative cAMP-dependent kinase phosphorylation site of Drosophila Rap1 can still rescue the Rap1 mutant phenotype. Our experiments show that Rap1 is not needed for cell proliferation and cell-fate specification but demonstrate a critical function for Rap1 in regulating normal morphogenesis in the eye disk, the ovary and the embryo. Rap1 mutations also disrupt cell migrations and cause abnormalities in cell shape. These findings indicate a role for Rap proteins as regulators of morphogenesis in vivo.

Amino Acid Sequence↗
PubMed2003

A novel cell binding site in the coiled-coil domain of laminin involved in capillary morphogenesis.

Recently, we reported the isolation and characterization of an anti-laminin antibody that modulates the extracellular matrix-dependent morphogenesis of endothelial cells. Here we use this antibody to precisely map the binding site responsible for mediating this biologically important interaction. By using a phage display-assisted mapping strategy to preserve protein structure, we demonstrate for the first time that the coiled-coil region of laminin contains a cell binding site. The adhesion motif is formed by residues contributed by both alpha and gamma chains, and is located in the middle part of the rod-like portion in a highly flexible area, which corresponds to a protease-susceptible site. Based on this information, a peptide mimotope was used to characterize the cognate receptor. Although we can not rule out the implication of other receptors, our results demonstrate that the laminin helical rod active site interacts with alpha2beta1 integrin on the surface of endothelial cells. These findings provide new insight into the complex mechanisms regulating capillary morphogenesis.

Amino Acid Sequence↗
PubMed1991

Pseudoreversion analysis indicates a direct role of cell division genes in polar morphogenesis and differentiation in Caulobacter crescentus.

A pseudoreversion analysis was used to examine the role of cell division genes in polar morphogenesis in Caulobacter crescentus. Extragenic suppressors of temperature sensitive mutations in pleC, a pleiotropic gene required for cell motility, formation of polar phi CbK bacteriophage receptors, and stalk formation, were isolated. These suppressors, which restored motility at 37 degrees C, simultaneously conferred a cold sensitive cell division phenotype and they were mapped to the three new cell division genes divJ, divL and divK. The cold-sensitive mutations in divL, and to a lesser extent divJ, exhibited a relatively narrow range of suppression. The cold-sensitive cell division mutation in divK, by contrast, suppressed all pleC mutations examined and behaved as a classical bypass suppressor. The direct role of this cell division gene in the regulation of motility is suggested by the observation that divK341 mapped to the same locus as pleD301, a pleiotropic mutation that prevents loss of motility and stalk formation. These results provide strong evidence that the cell division and developmental pathways are interconnected and they support our earlier conclusion that cell division is required for the regulation of polar morphogenesis and differentiation in C. crescentus.

Caulobacter↗
PubMed1995

Genomic regions required for morphogenesis of the Drosophila embryonic midgut.

The Drosophila midgut is an excellent system for studying the cell migration, cell-cell communication, and morphogenetic events that occur in organ formation. Genes representative of regulatory gene families common to all animals, including homeotic, TGF beta, and Wnt genes, play roles in midgut development. To find additional regulators of midgut morphogenesis, we screened a set of genomic deficiencies for midgut phenotypes. Fifteen genomic intervals necessary for proper midgut morphogenesis were identified, three contain genes already known to act in the midgut. Three other genomic regions are required for formation of the endoderm or visceral mesoderm components of the midgut. Nine regions are required for proper formation of the midgut constrictions. The E75 ecdysone-induced gene, which encodes a nuclear receptor superfamily member, is the relevant gene in one region and is essential for proper formation of midgut constrictions. E75 acts downstream of the previously known constriction regulators or in parallel. Temporal hormonal control may therefore work in conjunction with spatial regulation by the homeotic genes in midgut development. Another genomic region is required to activate transcription of the homeotic genes Antp and Scr specifically in visceral mesoderm. The genomic regions identified by this screen provide a map to novel midgut development regulators.

Animals↗
PubMed1995

LAS1 is an essential nuclear protein involved in cell morphogenesis and cell surface growth.

Saccharomyces cerevisiae mutations that cause a requirement for SSD1-v for viability were isolated, yielding one new gene, LAS1, and three previously identified genes, SIT4, BCK1/SLK1, and SMP3. Three of these genes, LAS1, SIT4, and BCK1/SLK1, encode proteins that have roles in bud formation or morphogenesis. LAS1 is essential and loss of LAS1 function causes the cells to arrest as 80% unbudded cells and 20% large budded cells that accumulate many vesicles at the mother-daughter neck. Overexpression of LAS1 results in extra cell surface projections in the mother cell, alterations in actin and SPA2 localization, and the accumulation of electron-dense structures along the periphery of both the mother cell and the bud. The nuclear localization of LAS1 suggests a role of LAS1 for regulating bud formation and morphogenesis via the expression of components that function directly in these processes.

Amino Acid Sequence↗
PubMed1997

The mup-4 locus in Caenorhabditis elegans is essential for hypodermal integrity, organismal morphogenesis and embryonic body wall muscle position.

mup-4 is a member of a set of genes essential for correct embryonic body wall muscle cell positions in Caenorhabditis elegans. The mup-4 phenotype is variably expressed and three discrete arrest phenotypes arise during the phase of embryonic development when the worm elongates from a ball of cells to its worm shape (organismal morphogenesis). Mutants representing two of the phenotypic classes arrest without successful completion of elongation. Mutants of the third phenotypic class arrest after completion of elongation. Mutants that arrest after elongation display profound dorsal and ventral body wall muscle cell position abnormalities and a characteristic kinked body shape (the Mup phenotype) due to the muscle cell position abnormalities. Significantly, genetic mosaic analysis of mup-4 mutants demonstrates that mup-4 gene function is essential in the AB lineage, which generates most of the hypodermis (epidermis), a tissue with which muscle interacts. Consistent with the genetic mosaic data, phenotypic characterizations reveal that mutants have defects in hypodermal integrity and morphology. Our analyses support the conclusion that mup-4 is essential for hypodermal function and that this function is necessary for organismal morphogenesis and for the maintenance of body wall muscle position.

Alleles↗
PubMed1997

Mutations synthetically lethal with tpm1delta lie in genes involved in morphogenesis.

Yeast contains two genes, TPM1 and TPM2, encoding tropomyosins, either of which can provide an essential function in the yeast cytoskeleton. To elucidate more clearly the function of the major tropomyosin, encoded by TPM1, we have isolated mutations that confer synthetic lethality with the null mutant of TPM1. Here we describe a phenotypic and genetic analysis of mutations in TSL1/BEM2, TSL2, TSL3, TSL5, and TSL6 (tropomyosin synthetic lethal). All the mutants exhibit clear morphological and some actin cytoskeletal defects, but are not noticeably defective in secretion, endocytosis, or organelle segregation. The lethality conferred by tsl tpm1delta mutations could be specifically suppressed by either TPM1 or an additional copy of TPM2. This implies that the essential function compromised in the tsl tpm1delta constructs is the same essential function for which Tpm1p or Tpm2p is necessary. Synthetic interactions and unlinked noncomplementation were observed between the tsl mutants, suggesting that they participate in related functions involving morphogenesis. In support of this, tsl6-1 was identified as an allele of the nonessential gene SLT2 or MPK1 whose product is a MAP kinase regulating cell wall synthesis. These results indicate that this synthetic lethality approach provides a sensitive screen for the isolation of mutations affecting morphogenesis, many of which are likely to be in nonessential genes, like BEM2 and SLT2.

Actins↗
PubMed1999

Identification and characterization of genes required for hyphal morphogenesis in the filamentous fungus Aspergillus nidulans.

In the filamentous fungus Aspergillus nidulans, germination of an asexual conidiospore results in the formation of a hyphal cell. A key feature of spore germination is the switch from isotropic spore expansion to polarized apical growth. Here, temperature-sensitive mutations are used to characterize the roles of five genes (sepA, hypA, podB-podD) in the establishment and maintenance of hyphal polarity. Evidence that suggests that the hypA, podB, and sepA genes are required for multiple aspects of hyphal morphogenesis is presented. Notably, podB and sepA are needed for organization of the cytoskeleton at sites of polarized growth. In contrast, podC and podD encode proteins that appear to be specifically required for the establishment of hyphal polarity during spore germination. The role of sepA and the pod genes in controlling the spatial pattern of polarized morphogenesis in germinating spores is also described. Results obtained from these experiments indicate that the normal pattern of germ-tube emergence is dependent upon the integrity of the actin cytoskeleton.

Aspergillus↗
PubMed2000

Embryonic morphogenesis in Caenorhabditis elegans integrates the activity of LET-502 Rho-binding kinase, MEL-11 myosin phosphatase, DAF-2 insulin receptor and FEM-2 PP2c phosphatase.

let-502 rho-binding kinase and mel-11 myosin phosphatase regulate Caenorhabditis elegans embryonic morphogenesis. Genetic analysis presented here establishes the following modes of let-502 action: (i) loss of only maternal let-502 results in abnormal early cleavages, (ii) loss of both zygotic and maternal let-502 causes elongation defects, and (iii) loss of only zygotic let-502 results in sterility. The morphogenetic function of let-502 and mel-11 is apparently redundant with another pathway since elimination of these two genes resulted in progeny that underwent near-normal elongation. Triple mutant analysis indicated that unc-73 (Rho/Rac guanine exchange factor) and mlc-4 (myosin light chain) act in parallel to or downstream of let-502/mel-11. In contrast mig-2 (Rho/Rac), daf-2 (insulin receptor), and age-1 (PI3 kinase) act within the let-502/mel-11 pathway. Mutations in the sex-determination gene fem-2, which encodes a PP2c phosphatase (unrelated to the MEL-11 phosphatase), enhanced mutations of let-502 and suppressed those of mel-11. fem-2's elongation function appears to be independent of its role in sexual identity since the sex-determination genes fem-1, fem-3, tra-1, and tra-3 had no effect on mel-11 or let-502. By itself, fem-2 affects morphogenesis with low penetrance. fem-2 blocked the near-normal elongation of let-502; mel-11 indicating that fem-2 acts in a parallel elongation pathway. The action of two redundant pathways likely ensures accurate elongation of the C. elegans embryo.

Amino Acid Sequence↗
PubMed2001

Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis.

Little is known about the genes that interact with Ras signaling pathways to regulate morphogenesis. The synthesis of dorsal eggshell structures in Drosophila melanogaster requires multiple rounds of Ras signaling followed by dramatic epithelial sheet movements. We took advantage of this process to identify genes that link patterning and morphogenesis; we screened lethal mutations on the second chromosome for those that could enhance a weak Ras1 eggshell phenotype. Of 1618 lethal P-element mutations tested, 13 showed significant enhancement, resulting in forked and fused dorsal appendages. Our genetic and molecular analyses together with information from the Berkeley Drosophila Genome Project reveal that 11 of these lines carry mutations in previously characterized genes. Three mutations disrupt the known Ras1 cell signaling components Star, Egfr, and Blistered, while one mutation disrupts Sec61beta, implicated in ligand secretion. Seven lines represent cell signaling and cytoskeletal components that are new to the Ras1 pathway; these are Chickadee (Profilin), Tec29, Dreadlocks, POSH, Peanut, Smt3, and MESK2, a suppressor of dominant-negative Ksr. A twelfth insertion disrupts two genes, Nrk, a "neurospecific" receptor tyrosine kinase, and Tpp, which encodes a neuropeptidase. These results suggest that Ras1 signaling during oogenesis involves novel components that may be intimately associated with additional signaling processes and with the reorganization of the cytoskeleton. To determine whether these Ras1 Enhancers function upstream or downstream of the Egf receptor, four mutations were tested for their ability to suppress an activated Egfr construct (lambdatop) expressed in oogenesis exclusively in the follicle cells. Mutations in Star and l(2)43Bb had no significant effect upon the lambdatop eggshell defect whereas smt3 and dock alleles significantly suppressed the lambdatop phenotype.

Animals↗
PubMed2002

The bereft gene, a potential target of the neural selector gene cut, contributes to bristle morphogenesis.

The neural selector gene cut, a homeobox transcription factor, is required for the specification of the correct identity of external (bristle-type) sensory organs in Drosophila. Targets of cut function, however, have not been described. Here, we study bereft (bft) mutants, which exhibit loss or malformation of a majority of the interommatidial bristles of the eye and cause defects in other external sensory organs. These mutants were generated by excising a P element located at chromosomal location 33AB, the enhancer trap line E8-2-46, indicating that a gene near the insertion site is responsible for this phenotype. Similar to the transcripts of the gene nearest to the insertion, reporter gene expression of E8-2-46 coincides with Cut in the support cells of external sensory organs, which secrete the bristle shaft and socket. Although bft transcripts do not obviously code for a protein product, its expression is abolished in bft deletion mutants, and the integrity of the bft locus is required for (interommatidial) bristle morphogenesis. This suggests that disruption of the bft gene is the cause of the observed bristle phenotype. We also sought to determine what factors regulate the expression of bft and the enhancer trap line. The correct specification of individual external sensory organ cells involves not only cut, but also the lineage genes numb and tramtrack. We demonstrate that mutations of these three genes affect the expression levels at the bft locus. Furthermore, cut overexpression is sufficient to induce ectopic bft expression in the PNS and in nonneuronal epidermis. On the basis of these results, we propose that bft acts downstream of cut and tramtrack to implement correct bristle morphogenesis.

Amino Acid Sequence↗
PubMed2002

Functional polycystin-1 expression is developmentally regulated during epithelial morphogenesis in vitro: downregulation and loss of membrane localization during cystogenesis.

Polycystin-1 is a protein mutated in the majority of cases of autosomal dominant polycystic kidney disease (ADPKD), but its role in the molecular pathway of tubulogenesis and cystogenesis is not understood. To define the role of polycystin-1 during dynamic changes in formation of intercellular contacts and cell polarity accompanying epithelial morphogenesis, we have utilized a 3D MDCK in vitro model of tubulogenesis and cystogenesis. Here we demonstrate that polycystin-1 is a novel component of desmosomal junctions of epithelial cells. A striking downregulation of polycystin-1 mRNA was detected in cysts as compared to tubules, leading to altered protein expression and localization. While polycystin-1 is localized to basolateral membranes of MDCK tubules, it is only detected in cytoplasmic pools in cystic cells. Furthermore, the expression of polycystin-1 is modulated during distinct stages of HGF-induced tubulogenesis from MDCK cysts. Thus, polycystin-1 is not detected in intercellular contacts at early steps of tubulogenesis, but assumes its basolateral localization at the time of cell polarization and lumen formation. An important role of polycystin-1 is further demonstrated using the pancreatic ductal epithelial cell line SU.86.86 which undergoes in vitro differentiation resulting in the formation of domes. Dome formation is thought to parallel tubular differentiation and morphogenesis in vivo. Our data reveal significant upregulation of polycystin-1 mRNA and protein levels in domes. Collectively, our results demonstrate a critical importance of controlled level of polycystin-1 expression for proper tubular differentiation and maturation. We suggest that the loss of polycystin-1 from its basolateral location in tubular epithelium may alter critical pathways controlling normal tubulogenesis leading to cystic transformation.

Adherens Junctions↗
PubMed2004

Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis.

The forkhead transcription factor FOXE1 is mutated in patients with Bamforth-Lazarus syndrome that exhibit hair follicle defects, suggesting a possible role for Foxe1 in hair follicle morphogenesis. Here, we report that Foxe1 is specifically expressed in the lower undifferentiated compartment of the hair follicle, at a time and site that parallel activation of the Shh signaling pathway. The Foxe1 protein is also expressed in human and mouse basal cell carcinoma in which hedgehog signaling is constitutively activated, whereas it is undetectable in normal epidermis and squamous cell carcinoma. Moreover, expression of a dominant-negative form of Gli2 in skin results in complete suppression of Foxe1 expression in the hair follicle, whereas transcriptionally active Gli2 stimulates activity of the Foxe1 promoter. Foxe1-null skin displays aberrant hair formation with the production of thinner and curly pelage hairs. Although the hair follicle internal structure is conserved and several lineage markers are properly expressed, the orderly downgrowth of follicles is strikingly disrupted, causing disorientation, misalignment and aberrantly shaped of hair follicles. Our findings provide a strong indication that the defect in Bamforth-Lazarus syndrome is due to altered FOXE1 function in the hair follicle, and is independent of systemic defects present in affected individuals. In addition, we establish Foxe1 as a downstream target of the Shh/Gli pathway in hair follicle morphogenesis, and as a crucial player for correct hair follicle orientation into the dermis and subcutis.

Animals↗
PubMed2006

Mathematical analysis of a free-boundary model for lung branching morphogenesis.

Lung branching morphogenesis has been widely studied in the field of developmental biology. Lung airway trees consist of relatively regular-sized distal branches, but how this regular branched pattern is formed is not well understood. In the present study, we undertake a detailed mathematical analysis of the model proposed in (Hartmann & Miura (2006), which numerically captures branching morphogenesis of the simplest possible experimental system in vitro. We investigate analytically the stability of 1D travelling waves with respect to periodic perturbations in two dimensions. This linear stability analysis leads to the so-called dispersion relations, predicting that a certain representative length dominates in this model. As the analytical analysis is restricted to travelling waves, we generalize the linear analysis to any 1D solution by numerical simulations. Both results predict how the representative lengths will change by experimentally changing specific parameters. Finally, we discuss the importance of the analytical results from a biological point of view and propose an experimental scheme for a quantitative comparison between experiments and theory.

Algorithms↗
PubMed2006

Characterization of tomato (Solanum lycopersicum L.) mutants affected in their flowering time and in the morphogenesis of their reproductive structure.

The impact of the season on flowering time and the organization and morphogenesis of the reproductive structures are described in three tomato mutants: compound inflorescence (s), single flower truss (sft), and jointless (j), respectively, compared with their wild-type cultivars Ailsa Craig (AC), Platense (Pl), and Heinz (Hz). In all environmental conditions, the sft mutant flowered significantly later than its corresponding Pl cultivar while flowering time in j was only marginally, but consistently, delayed compared with Hz. The SFT gene and, to a lesser extent, the J gene thus appear to be constitutive flowering promoters. Flowering in s was delayed in winter but not in summer compared with the AC cultivar, suggesting the existence of an environmentally regulated pathway for the control of floral transition. The reproductive structure of tomato is a raceme-like inflorescence and genes regulating its morphogenesis may thus be divided into inflorescence and floral meristem identity genes as in Arabidopsis. The s mutant developed highly branched inflorescences bearing up to 200 flowers due to the conversion of floral meristems into inflorescence meristems. The S gene appears to be a floral meristem identity gene. Both sft and j mutants formed reproductive structures containing flowers and leaves and reverting to a vegetative sympodial growth. The SFT gene appears to regulate the identity of the inflorescence meristem of tomato and is also involved, along with the J gene, in the maintenance of this identity, preventing reversion to a vegetative identity. These results are discussed in relation to knowledge accumulated in Arabidopsis and to domestication processes.

DNA, Complementary↗