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Vienna, Austria

Townley A.K.,University of Bristol | Schmidt K.,University of Bristol | Schmidt K.,Max F Perutz Laboratories | Hodgson L.,University of Bristol | Stephens D.J.,University of Bristol
Journal of Cell Science | Year: 2012

Epithelial morphogenesis is directed by interactions with the underlying extracellular matrix. Secretion of collagen and other matrix components requires efficient coat complex II (COPII) vesicle formation at the endoplasmic reticulum. Here, we show that suppression of the outer layer COPII component, Sec13, in zebrafish embryos results in a disorganized gut epithelium. In human intestinal epithelial cells (Caco-2), Sec13 depletion causes defective epithelial polarity and organization on permeable supports. Defects are seen in the ability of cells to adhere to the substrate, form a monolayer and form intercellular junctions. When embedded in a three-dimensional matrix, Sec13-depleted Caco-2 cells form cysts but, unlike controls, are defective in lumen expansion. Incorporation of primary fibroblasts within the three-dimensional culture substantially restores normal morphogenesis. We conclude that efficient COPIIdependent secretion, notably assembly of Sec13-Sec31, is required to drive epithelial morphogenesis in both two- and three-dimensional cultures in vitro, as well as in vivo. Our results provide insight into the role of COPII in epithelial morphogenesis and have implications for the interpretation of epithelial polarity and organization assays in cell culture. © 2012. Source


Yang H.,Chonnam National University | Tong J.,Chonnam National University | Leonard T.A.,Max F Perutz Laboratories | Im Y.J.,Chonnam National University
FEBS Letters | Year: 2013

Sec14 family homologs are the major yeast phosphatidylinositol/ phosphatidylcholine transfer proteins regulating lipid metabolism and vesicle trafficking. The structure of Saccharomyces cerevisiae Sfh3 displays a conserved Sec14 scaffold and reveals determinants for the specific recognition of phosphatidylinositol ligand. Apo-Sfh3 forms a dimer through the hydrophobic interaction of gating helices. Binding of phosphatidylinositol leads to dissociation of the dimer into monomers in a reversible manner. This study suggests that the substrate induced dimer-monomer transformation is an essential part of lipid transfer cycles by Sfh3. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Source


Conduit P.T.,University of Oxford | Feng Z.,University of Oxford | Richens J.H.,University of Oxford | Baumbach J.,University of Oxford | And 6 more authors.
Developmental Cell | Year: 2014

Centrosomes are important cell organizers. They consist of a pair of centrioles surrounded by pericentriolar material (PCM) that expands dramatically during mitosis-a process termed centrosome maturation. How centrosomes mature remains mysterious. Here, we identify a domain in Drosophila Cnn that appears to be phosphorylated by Polo/Plk1 specifically at centrosomes during mitosis. The phosphorylation promotes the assembly of a Cnn scaffold around the centrioles that is in constant flux, with Cnn molecules recruited continuously around the centrioles as the scaffold spreads slowly outward. Mutations that block Cnn phosphorylation strongly inhibit scaffold assembly and centrosome maturation, whereas phosphomimicking mutations allow Cnn to multimerize invitro and to spontaneously form cytoplasmic scaffolds invivo that organize microtubules independently of centrosomes. We conclude that Polo/Plk1 initiates the phosphorylation-dependent assembly of a Cnn scaffold around centrioles that is essential for efficient centrosome maturation in flies. © 2014 The Authors. Source


Matuszewski S.,University of Vienna | Hermisson J.,University of Vienna | Hermisson J.,Max F Perutz Laboratories | Kopp M.,Aix - Marseille University
Genetics | Year: 2015

Adaptation lies at the heart of Darwinian evolution. Accordingly, numerous studies have tried to provide a formal framework for the description of the adaptive process. Of these, two complementary modeling approaches have emerged: While socalled adaptive-walk models consider adaptation from the successive fixation of de novo mutations only, quantitative genetic models assume that adaptation proceeds exclusively from preexisting standing genetic variation. The latter approach, however, has focused on short-term evolution of population means and variances rather than on the statistical properties of adaptive substitutions. Our aim is to combine these two approaches by describing the ecological and genetic factors that determine the genetic basis of adaptation from standing genetic variation in terms of the effect-size distribution of individual alleles. Specifically, we consider the evolution of a quantitative trait to a gradually changing environment. By means of analytical approximations, we derive the distribution of adaptivesubstitutions from standing genetic variation, that is, the distribution of the phenotypic effects of those alleles from the standing variation that become fixed during adaptation. Our results are checked against individual-based simulations. We find that, compared to adaptation from de novo mutations, (i) adaptation from standing variation proceeds by the fixation of more alleles of small effect and (ii) populations that adapt from standing genetic variation can traverse larger distances in phenotype space and, thus, have a higher potential for adaptation if the rate of environmental change is fast rather than slow. © 2015 by the Genetics Society of America. Source


Tobler R.,Institute For Populationsgenetik | Franssen S.U.,Institute For Populationsgenetik | Kofler R.,Institute For Populationsgenetik | Orozco-Terwengel P.,Institute For Populationsgenetik | And 5 more authors.
Molecular Biology and Evolution | Year: 2014

Experimental evolution in combination with whole-genome sequencing (evolve and resequence [E&R]) is a promising approach to define the genotype-phenotype map and to understand adaptation in evolving populations. Many previous studies have identified a large number of putative selected sites (i.e., candidate loci), but it remains unclear to what extent these loci are genuine targets of selection or experimental noise. To address this question, we exposed the same founder population to two different selection regimes-a hot environment and a cold environment-and quantified the genomic response in each. We detected large numbers of putative selected loci in both environments, albeit with little overlap between the two sets of candidates, indicating that most resulted from habitat-specific selection. By quantifying changes across multiple independent biological replicates, we demonstrate that most of the candidate SNPs were false positives that were linked to selected sites over distances much larger than the typical linkage disequilibrium range of Drosophila melanogaster. We show that many of these mid-to long-range associations were attributable to large segregating inversions and confirm by computer simulations that such patterns could be readily replicated when strong selection acts on rare haplotypes. In light of our findings, we outline recommendations to improve the performance of future Drosophila EandR studies which include using species with negligible inversion loads, such as D. mauritiana and D. simulans, instead of D. melanogaster. © 2013 The Author. Source

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