@article{4149, abstract = {An important step in the formation of all epithelial organs is the coordinated polarisation of their constituent cells. One of the factors thought to be crucial for this process is the extracellular matrix (ECM), which provides positional information for cells and directs polarity specification and epithelial cyst formation in 3D culture. However, in vivo evidence for the role of the ECM in epithelial tissue polarisation is scarce. To gain insight in the factors involved in establishing cell polarity during organogenesis, we are studying a group of epithelial cells called the Dorsal Forerunner Cells (DFCs) in zebrafish embryos. These cells migrate as a cluster towards the vegetal pole of the developing embryo, where they involute. During this process they polarise, and make foci that open up to form a ciliated lumen called Kupffer’s vesicle. We find that interfering with the deposition of components of the extracellular matrix, or with the intracellular anchors of the cells to the matrix, impairs the polarisation of the DFC’s and leads to subsequent defects in lumen formation. In addition, we have developed a method to culture the DFCs ex vivo, allowing us to precisely manipulate the extracellular environment. The possibility of combining the genetic study of Kupffer’s vesicle formation in the live embryo with cell biological techniques in organ culture make this system uniquely relevant for studying the role of the ECM in polarisation during organogenesis. }, author = {Soete, Gwen and Heisenberg, Carl-Philipp J}, journal = {Mechanisms of Development}, pages = {S168 -- S168}, publisher = {Elsevier}, title = {{The role of the extracellular matrix in Kupffer's vesicle formation in zebrafish}}, doi = {10.1016/j.mod.2009.06.391}, volume = {126}, year = {2009}, } @article{4158, abstract = {Together with cell growth, division and death, changes in cell shape are of central importance for tissue morphogenesis during development. Cell shape is the product of a cell's material and active properties balanced by external forces. Control of cell shape, therefore, relies on both tight regulation of intracellular mechanics and the cell's physical interaction with its environment. In this review, we first discuss the biological and physical mechanisms of cell shape control. We next examine a number of develop mental processes in which cell shape change - either individually or in a coordinated manner - drives embryonic morphogenesis and discuss how cell shape is controlled in these processes. Finally, we emphasize that cell shape control during tissue morphogenesis can only be fully understood by using a combination of cellular, molecular, developmental and biophysical approaches.}, author = {Paluch, Ewa and Heisenberg, Carl-Philipp J}, journal = {Current Biology}, number = {17}, pages = {R790 -- R799}, publisher = {Cell Press}, title = {{Biology and physics of cell shape changes in development}}, doi = {10.1016/j.cub.2009.07.029}, volume = {19}, year = {2009}, } @article{4159, abstract = {Apical cell contraction triggers tissue folding and invagination in epithelia. During Drosophila gastrulation, ventral furrow formation was thought to be driven by smooth, purse-string-like constriction of an actomyosin belt underlying adherens junctions. Now Martin et al. report in Nature that ventral furrow formation is triggered by asynchronous pulsed contractions of the apical acto-myosin cortex in individual cells.}, author = {Paluch, Ewa and Heisenberg, Carl-Philipp J}, journal = {Developmental Cell}, number = {1}, pages = {4 -- 6}, publisher = {Cell Press}, title = {{Chaos begets order: Asynchronous cell contractions drive epithelial morphogenesis}}, doi = {10.1016/j.devcel.2008.12.011}, volume = {16}, year = {2009}, } @article{4160, abstract = {While the function of patterning in organogenesis is being extensively studied, considerably less is known of reverse effects that organ formation imposes on patterning. In zebrafish, the Kupffer’s vesicle (KV) and parapineal (PP) are embryonic struc- tures that share mechanisms of organogenesis and whose func- tion is essential for normal patterning along the left–right axis. Early morphogenesis of KV and PP organs involve the compaction of progenitor cells into a tight cluster within which three-dimen- sional cellular rosettes are formed. Organisation into rosettes pre- cedes the detachment of progenitor cells from neighbouring tissue and thus represents a key step towards organ formation. Such morphogenetic event is essential for organ function and its disruption has profound effects on left–right patterning.}, author = {Oteíza, Pablo and Lemus, Carmen and Köppen, Mathias and Palma, Karina and Krieg, Michael and Melo, Cristina and Farias, Cecilia and Pulgar, Eduardo and Preibisch, Steffen and Hartel, Steffen and Heisenberg, Carl-Philipp J and Concha, Miguel}, journal = {Mechanisms of Development}, number = {Supplement 1}, pages = {S11 -- S11}, publisher = {Elsevier}, title = {{Linking organ formation to left-right patterning in the embryonic zebrafish}}, doi = {10.1016/j.mod.2009.06.970}, volume = {126}, year = {2009}, } @article{4162, abstract = {Organ formation requires the precise assembly of progenitor cells into a functional unit. Mechanical forces are likely to play a critical role in this process, but it is unclear how these are molecularly controlled during development. Here, we show that Wnt11/ Pk1a-mediated planar cell polarity (PCP) signalling coordinates formation of the zebrafish laterality organ (Kupffer’s vesicle, KV) by regulating adhesion forces between organ progenitor cells (the dorsal forerunner cells, DFCs).}, author = {Oteíza, Pablo and Köppen, Mathias and Krieg, Michael and Preibisch, Steffen and Haertel, Steffen and Müller, Daniel and Heisenberg, Carl-Philipp J and Concha, Miguel}, journal = {Mechanisms of Development}, number = {Supplement 1}, pages = {S80 -- S80}, publisher = {Elsevier}, title = {{Wnt11/Pk1a-mediated planar cell polarity signalling orchestrates epithelial organ morphogenesis by regulating N-cadherin dependent cell adhesion forces}}, doi = {10.1016/j.mod.2009.06.098}, volume = {126}, year = {2009}, } @article{4165, abstract = {The tissues of a developing embryo are simultaneously patterned, moved and differentiated according to an exchange of information between their constituent cells. We argue that these complex self-organizing phenomena can only be fully understood with quantitative mathematical frameworks that allow specific hypotheses to be formulated and tested. The quantitative and dynamic imaging of growing embryos at the molecular, cellular and tissue level is the key experimental advance required to achieve this interaction between theory and experiment. Here we describe how mathematical modelling has become an invaluable method to integrate quantitative biological information across temporal and spatial scales, serving to connect the activity of regulatory molecules with the morphological development of organisms.}, author = {Oates, Andrew and Gorfinkiel, Nicole and Gonzalez Gaitan, Marcos and Heisenberg, Carl-Philipp J}, journal = {Nature Reviews Genetics}, number = {8}, pages = {517 -- 530}, publisher = {Nature Publishing Group}, title = {{Quantitative approaches in developmental biology}}, doi = {10.1038/nrg2548}, volume = {10}, year = {2009}, } @article{4192, abstract = {During vertebrate gastrulation, the body axis is established by a variety of co-ordinated and directed movements of cells. One of these movements is convergence and extension (CE), which is regulated by a non-canonical Wnt/planar cell polarity (PCP) pathway. From our forward genetic screen, we have identified 3-hydroxy-3-methyglutaryl-coenzyme A reductase 1b (hmgcr1b) gene as a dominant enhancer of the silberblick (slb)/wnt11 CE phenotype. hmgcr1b mutant embryos exhibit only very mild CE phenotype during gastrulation while showing a thicker yolk extension at pharyngula stages. Notably, abrogation of hmgcr1b also enhances the CE defects of other core PCP mutants/morphants. The prenylation pathway is one of branches downstream of HMGCR, and has been implicated for lipid modification at the C-terminus of proteins. To test the possibility that the prenylation pathway regulates activities of the PCP pathway, we abrogated farnesyl transferase (FT) or geranylgeranyl transferase (GGT) function using morpholinos on PCP mutant/morphant backgrounds. Consistent with the notion that FT preferentially performs lipid modification on to proteins with the CAAX motif including the core PCP protein Prickle (Pk), abrogation of FT, but not GGT, enhances the pk1a or pk1b morphant CE phenotype, suggesting the specif icity for targets of the prenylation enzymes. }, author = {Kai, Masatake and Buchan, Nina and Heisenberg, Carl-Philipp J and Tada, Masazumi}, journal = {Mechanisms of Development}, number = {Supplement 1}, pages = {S132 -- S132}, publisher = {Elsevier}, title = {{Regulation of planar cell polarity signalling by the prenylation pathway}}, doi = {10.1016/j.mod.2009.06.269}, volume = {126}, year = {2009}, } @article{4206, abstract = {Dorsal closure (DC), the closure of a hole in the dorsal epidermis of Drosophila embryos by the joining of opposing epithelial cell sheets, has been used as a model process to study the molecular and cellular mechanisms underlying epithelial spreading and wound healing. Recent studies have provided novel insights into how different tissues function cooperatively in this process. Specifically, they demonstrate a critical function of the epidermis surrounding the hole in modulating the behavior of the amnioserosa cells inside. These findings shed light not only on the mechanisms by which the behavior of different tissues is coordinated during DC, but also on the general mechanisms by which tissues interact to trigger global morphogenesis, an essential but yet poorly explored aspect of embryogenesis.}, author = {Heisenberg, Carl-Philipp J}, journal = {Bioessays : News and Reviews in Molecular, Cellular and Developmental Biology}, number = {12}, pages = {1284 -- 1287}, publisher = {Wiley-Blackwell}, title = {{Dorsal closure in Drosophila: cells cannot get out of the tight spot}}, doi = {10.1002/bies.200900109}, volume = {31}, year = {2009}, } @article{4217, abstract = {Nuclear movements play an essential role in metazoan development. Although the intracellular transport mechanisms underlying nuclear movements have been studied in detail, relatively little is known about signals from surrounding cells and tissues controlling these movements. Here, we show that, in gastrulating zebrafish embryos, convergence movements of nuclei within the yolk syncytial layer (YSL) are guided by mesoderm and endoderm progenitors migrating along the surface of the yolk towards the dorsal side of the developing gastrula. Progenitor cells direct the convergence movements of internal yolk syncytial nuclei (iYSN) by modulating cortical flow within the YSL in which the iYSN are entrained. The effect of mesoderm and endoderm progenitors on the convergence movement of iYSN depends on the expression of E-cadherin, indicating that adhesive contact between the cells and the YSL is required for the mesendoderm-modulated YSL cortical flow mediating nuclear convergence. In summary, our data reveal a crucial function for cortical flow in the coordination of syncytial nuclear movements with surrounding cells and tissues during zebrafish gastrulation.}, author = {Carvalho, Lara and Stuehmer, Jan and Bois, Justin and Kalaidzidis, Yannis and Lecaudey, Virginie and Heisenberg, Carl-Philipp J}, journal = {Development}, number = {8}, pages = {1305 -- 1315}, publisher = {Company of Biologists}, title = {{Control of convergent yolk syncytial layer nuclear movement in zebrafish}}, doi = {10.1242/dev.026922}, volume = {136}, year = {2009}, } @article{4223, abstract = {Both Gram-positive and Gram-negative bacteria contain bactoprenol-dependent biosynthetic pathways expressing non-essential cell surface polysaccharides that function as virulence factors. Although these polymers are not required for bacterial viability in vitro, genes in many of the biosynthetic pathways are conditionally essential: they cannot be deleted except in strains incapable of initiating polymer synthesis. We report a cell-based, pathway-specific strategy to screen for small molecule inhibitors of conditionally essential enzymes. The screen identifies molecules that prevent the growth of a wildtype bacterial strain but do not affect the growth of a mutant strain incapable of initiating polymer synthesis. We have applied this approach to discover inhibitors of wall teichoic acid (WTA) biosynthesis in Staphylococcus aureus. WTAs are anionic cell surface polysaccharides required for host colonization that have been suggested as targets for new antimicrobials. We have identified a small molecule, 7-chloro-N,N-diethyl-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5-a]quinolin-5-amine (1835F03), that inhibits the growth of a panel of S. aureus strains (MIC = 1−3 μg mL−1), including clinical methicillin-resistant S. aureus (MRSA) isolates. Using a combination of biochemistry and genetics, we have identified the molecular target as TarG, the transmembrane component of the ABC transporter that exports WTAs to the cell surface. We also show that preventing the completion of WTA biosynthesis once it has been initiated triggers growth arrest. The discovery of 1835F03 validates our chemical genetics strategy for identifying inhibitors of conditionally essential enzymes, and the strategy should be applicable to many other bactoprenol-dependent biosynthetic pathways in the pursuit of novel antibacterials and probes of bacterial stress responses.}, author = {Swoboda, Jonathan and Meredith, Timothy and Campbell, Jennifer and Brown, Stephanie and Suzuki, Takashi and Bollenbach, Mark Tobias and Malhowski, Amy and Kishony, Roy and Gilmore, Michael and Walker, Suzanne}, journal = {ACS Chemical Biology}, number = {10}, pages = {875 -- 883}, publisher = {American Chemical Society}, title = {{Discovery of a Small Molecule that Blocks Wall Teichoic Acid Biosynthesis in Staphylococcus aureus}}, doi = {10.1021/cb900151k}, volume = {4}, year = {2009}, } @article{4228, abstract = {Suppressive drug interactions, in which one antibiotic can actually help bacterial cells to grow faster in the presence of another, occur between protein and DNA synthesis inhibitors. Here, we show that this suppression results from nonoptimal regulation of ribosomal genes in the presence of DNA stress. Using GFP-tagged transcription reporters in Escherichia coli, we find that ribosomal genes are not directly regulated by DNA stress, leading to an imbalance between cellular DNA and protein content. To test whether ribosomal gene expression under DNA stress is nonoptimal for growth rate, we sequentially deleted up to six of the seven ribosomal RNA operons. These synthetic manipulations of ribosomal gene expression correct the protein-DNA imbalance, lead to improved survival and growth, and completely remove the suppressive drug interaction. A simple mathematical model explains the nonoptimal regulation in different nutrient environments. These results reveal the genetic mechanism underlying an important class of suppressive drug interactions.}, author = {Bollenbach, Tobias and Quan, Selwyn and Remy Chait and Kishony, Roy}, journal = {Cell}, number = {4}, pages = {707 -- 718}, publisher = {Cell Press}, title = {{Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions}}, doi = {10.1016/j.cell.2009.10.025}, volume = {139}, year = {2009}, } @article{4231, abstract = {The evolution of quantitative characters depends on the frequencies of the alleles involved, yet these frequencies cannot usually be measured. Previous groups have proposed an approximation to the dynamics of quantitative traits, based on an analogy with statistical mechanics. We present a modified version of that approach, which makes the analogy more precise and applies quite generally to describe the evolution of allele frequencies. We calculate explicitly how the macroscopic quantities (i.e., quantities that depend on the quantitative trait) depend on evolutionary forces, in a way that is independent of the microscopic details. We first show that the stationary distribution of allele frequencies under drift, selection, and mutation maximizes a certain measure of entropy, subject to constraints on the expectation of observable quantities. We then approximate the dynamical changes in these expectations, assuming that the distribution of allele frequencies always maximizes entropy, conditional on the expected values. When applied to directional selection on an additive trait, this gives a very good approximation to the evolution of the trait mean and the genetic variance, when the number of mutations per generation is sufficiently high (4Nμ > 1). We show how the method can be modified for small mutation rates (4Nμ → 0). We outline how this method describes epistatic interactions as, for example, with stabilizing selection.}, author = {Barton, Nicholas H and De Vladar, Harold}, journal = {Genetics}, number = {3}, pages = {997 -- 1011}, publisher = {Genetics Society of America}, title = {{Statistical mechanics and the evolution of polygenic quantitative traits}}, doi = {10.1534/genetics.108.099309}, volume = {181}, year = {2009}, } @phdthesis{4232, author = {Harold Vladar}, publisher = {Faculty of mathematical and natural sciences, University of Groningen}, title = {{Stochasticity and Variability in the dynamics and genetics of populations}}, doi = {3811}, year = {2009}, } @article{4242, abstract = {Felsenstein distinguished two ways by which selection can directly strengthen isolation. First, a modifier that strengthens prezygotic isolation can be favored everywhere. This fits with the traditional view of reinforcement as an adaptation to reduce deleterious hybridization by strengthening assortative mating. Second, selection can favor association between different incompatibilities, despite recombination. We generalize this “two allele” model to follow associations among any number of incompatibilities, which may include both assortment and hybrid inviability. Our key argument is that this process, of coupling between incompatibilities, may be quite different from the usual view of reinforcement: strong isolation can evolve through the coupling of any kind of incompatibility, whether prezygotic or postzygotic. Single locus incompatibilities become coupled because associations between them increase the variance in compatibility, which in turn increases mean fitness if there is positive epistasis. Multiple incompatibilities, each maintained by epistasis, can become coupled in the same way. In contrast, a single-locus incompatibility can become coupled with loci that reduce the viability of haploid hybrids because this reduces harmful recombination. We obtain simple approximations for the limits of tight linkage, and strong assortment, and show how assortment alleles can invade through associations with other components of reproductive isolation.}, author = {Barton, Nicholas H and De Cara, Maria}, journal = {Evolution; International Journal of Organic Evolution}, number = {5}, pages = {1171 -- 1190}, publisher = {Wiley}, title = {{The evolution of strong reproductive isolation}}, doi = {10.1111/j.1558-5646.2009.00622.x}, volume = {63}, year = {2009}, } @article{4357, abstract = {Parallel evolution is the acquisition of identical adaptive traits in independently evolving populations. Understanding whether the genetic changes underlying adaptation to a common selective environment are parallel within and between species is interesting because it sheds light on the degree of evolutionary constraints. If parallel evolution is perfect, then the implication is that forces such as functional constraints, epistasis, and pleiotropy play an important role in shaping the outcomes of adaptive evolution. In addition, population genetic theory predicts that the probability of parallel evolution will decline with an increase in the number of adaptive solutions-if a single adaptive solution exists, then parallel evolution will be observed among highly divergent species. For this reason, it is predicted that close relatives-which likely overlap more in the details of their adaptive solutions-will show more parallel evolution. By adapting three related bacteriophage species to a novel environment we find (1) a high rate of parallel genetic evolution at orthologous nucleotide and amino acid residues within species, (2) parallel beneficial mutations do not occur in a common order in which they fix or appear in an evolving population, (3) low rates of parallel evolution and convergent evolution between species, and (4) the probability of parallel and convergent evolution between species is strongly effected by divergence.}, author = {Jonathan Bollback and Huelsenbeck, John P}, journal = {Genetics}, number = {1}, pages = {225 -- 234}, publisher = {Genetics Society of America}, title = {{Parallel genetic evolution within and between bacteriophage species of varying degrees of divergence}}, doi = {10.1534/genetics.107.085225}, volume = {181}, year = {2009}, } @inproceedings{4360, author = {Thomas Wies and Piskac, Ruzica and Kuncak, Viktor}, pages = {366 -- 382}, publisher = {Springer}, title = {{Combining Theories with Shared Set Operations}}, doi = {1558}, year = {2009}, } @phdthesis{4363, author = {Vasu Singh}, booktitle = {Formalizing and Verifying Transactional Memories}, publisher = {EPFL Lausanne}, title = {{Formalizing and Verifying Transactional Memories}}, year = {2009}, } @inproceedings{4365, author = {Seghir,Mohamed Nassim and Podelski,Andreas and Thomas Wies}, pages = {3 -- 18}, publisher = {Springer}, title = {{Abstraction Refinement for Quantified Array Assertions}}, doi = {1556}, year = {2009}, } @inproceedings{4375, author = {Lahiri,Shuvendu K. and Qadeer,Shaz and Galeotti,Juan P. and Voung,Jan W. and Thomas Wies}, pages = {493 -- 508}, publisher = {Springer}, title = {{Intra-module Inference}}, doi = {1555}, year = {2009}, } @inproceedings{4376, author = {Lublinerman,Roberto and Chaudhuri,Swarat and Pavol Cerny}, pages = {61 -- 80}, publisher = {ACM}, title = {{Parallel programming with object assemblies}}, doi = {1546}, year = {2009}, }