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Structure-function Analysis Of The Drosophila Stubble Type Ii Transmembrane Serine ProteaseMorgan, Rachel 01 January 2008 (has links)
Hormonally-triggered regulatory hierarchies play a major role in organismal development. Disruption of a single member of such a hierarchy can lead to irregular development and disease. Therefore, knowledge of the members involved and the mechanisms controlling signaling through such pathways is of great importance in understanding how resulting developmental defects occur. Type II transmembrane serine proteases (TTSPs) make up a family of cell surface-associated proteases that play important roles in the development and homeostasis of a number of mammalian tissues. Aberrant expression of TTSPs is linked to several human disorders, including deafness, heart and respiratory disease and cancer. However, the mechanism by which these proteases function remains unknown. The ecdysone-responsive Stubble TTSP of Drosophila serves as a good model in which to study the functional mechanism of the TTSP family. The Stubble protease interacts with the intracellular Rho1 (RhoA) pathway to control epithelial development in imaginal discs. The Rho1 signaling pathway regulates cellular behavior via control of gene expression and actin cytoskeletal dynamics. However, the mechanism by which the Stubble protease interacts with the Rho1 pathway to control epithelial development, in particular leg imaginal disc morphogenesis, has yet to be elucidated. The Stubble protein consists of several conserved domains. One approach to a better understanding of the mechanism of action of Stubble in regulating Rho1 signaling is to define which of the conserved domains within the protease are required for proper function. Sequence analysis of twelve recessive Stubble mutant alleles has revealed that the proteolytic domain is essential for proper function. Alleles containing mutations which disrupt regions of the protease domain necessary for protease activation or substrate binding, as well as those with deletions or truncations that remove some portion of the proteolytic domain, result in defective epithelial development in vivo. In contrast, mutations in other regions of the Stubble protein, including the disulfide-knotted and cytoplasmic domains, were not observed. Another important step for defining the connection between Stubble and Rho1 signaling is to identify a Stubble target that acts as an upstream regulator of the Rho1 pathway. We performed a genetic screen in which 97 of the 147 Drosophila non-olfactory and non-gustatory G-protein-coupled receptors (GPCRs), a family of proteins that has been shown to be protease-activated and to activate Rho1 signaling, were tested for interactions with a mutant allele of Stubble. We found 4 genomic regions uncovering a total of 7 GPCRs that interact genetically when in heterozygous combination with a Stubble mutant. Further analysis of these genes is necessary to determine if any of these GPCRs is targeted by Stubble during activation of the Rho1 pathway.
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On linear Reaction-Diffusion systems and Network ControllabilityAulin, Rebecka, Hage, Felicia January 2023 (has links)
In 1952 Alan Turing published his paper "The Chemical Basis of Morphogenesis", which described a model for how naturally occurring patterns, such as the stripes of a zebra and the spots of a leopard, can arise from a spatially homogeneous steady state through diffusion. Turing suggested that the concentration of the substances producing the patterns is determined by the reaction kinetics, how the substances interact, and diffusion. In this project Turing's model with linear reactions kinetics was studied. The model was first solved using two different numerical methods; the finite difference method (FDM) and the finite element method (FEM) with different boundary conditions. A parameter study was then conducted, investigating the effect on the patterns of changing the parameters of the model. Lastly the controllability of the model and the least energy control was considered. The simulations were found to produce patterns provided the right parameters, as expected. From the investigation of the parameters it could be concluded that the size/tightness of the pattern and similarity of the substance concentration distributions depended on the choice of parameters. As for the controllability, a desired final state could be produced thorough simulations using control of the boundary and the energy cost of producing the pattern increased when decreasing the number of controls.
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Analysis and mathematical modeling of silica morphogenesis in diatomsBabenko, Iaroslav 27 February 2024 (has links)
The silica-based cell walls of diatoms are prime examples of genetically controlled, species-specific mineral architectures. The physical principles underlying morphogenesis of their hierarchically structured silica patterns are not understood, yet such insight could reveal novel routes towards synthesizing functional inorganic materials. Recent advances in imaging nascent diatom silica allow rationalizing possible mechanisms of their pattern formation. Here, we combine theory and experiments on the model diatom Thalassiosira pseudonana to put forward a minimal model for morphogenesis of branched rib patterns – a widespread feature of diatom cell walls. To this end, we developed an automated image analysis algorithm that enabled quantitative assessment of the morphological discrepancy between the experiments and model predictions. The model proposed here quantitatively recapitulates the time-course of rib pattern formation by accounting for silica biochemistry with autocatalytic formation of diffusible silica precursors followed by conversion into solid silica. We propose that silica deposition releases an inhibitor that slows down up-stream precursor conversion, thereby implementing a self-replicating reaction-diffusion system, recapitulated by a non-classical Turing mechanism. The proposed mechanism highlights the role of geometrical cues for guided self-organization, rationalizing the instructive role for the single initial pattern seed known as primary silicification site present in diatoms. The model features a wide spectrum of possible pattern morphologies depending on the model parameters, suggesting that this model may be applicable in other diatom species. Moreover, due to the generic nature of the proposed model for branching morphogenesis, the mechanism identified here may be relevant also in other biological systems known to exhibit.
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A quantitative investigation of shape change in epithelial monolayersKrishna, Abhijeet 27 February 2024 (has links)
Epithelial tissues are one of the most abundant tissues in our body. They make up essential organs like the gut, heart and eyes. These organs take up their complex 3D shapes during normal development of the embryo. Our understanding of such large-scale 3D shape changes is limited mainly due to the technical difficulties of imaging and quantifying such developmental events. In this thesis, I study two events in which epithelial monolayers change their 3D shape. In both the projects, I use data from light-sheet microscopic images of developmental events. These data are provided by my collaborators. In this thesis, I further analyzed them using quantitative approaches and interpreted them using computational models.
In the first project, I study a case of a developing tissue inside a rigid confinement. A perfect model system for this is the Drosophila embryo which consists of an epithelial monolayer (blastoderm) inside a rigid shell (vitelline membrane). During gastrulation, the blastoderm is under compressional stresses due to tissue proliferation and compression from the germband extension. During this time, an invagination separating the future head and the trunk region appears. This is known as the cephalic furrow (CF). As the CF disappears after some time, its relevance in the normal development of the embryo is unclear.
To understand its role, my collaborators image the blastoderm in mutant embryos which lack CF. These mutant embryos have either of the genes even-skipped (eve) or buttonhead (btd) knocked down. In the absence of CF, temporary ectopic folds appear in the blastoderm in locations which vary between embryos. Unlike the CF, ectopic folds appear suddenly and hence look like buckling events.
I hypothesize that ectopic folds appear because of the compressive stresses generated in the blastoderm during the germband extension or by the compression of tissues that are adjacent to mitotic domains. Moreover, in normal embryos, CF, which is a controlled invagination, acts as a sink for the compressive stresses and thus suppresses ectopic folds. To test this hypothesis, I modelled the blastoderm as a 2D elastic tissue which is confined inside a rigid boundary acting as the vitelline membrane.
In my model, I show that the stresses generated by both the germband extension and the mitotic domains contribute to the formation of ectopic folds. I model the CF as a region with some preferred intrinsic curvature, thus acting as a programmed fold. I show that ectopic folds are inhibited in the presence of a CF. However, the efficiency of the CF depends on the strength of the CF and, interestingly, the timing of the CF. I observe that even a weak CF can inhibit ectopic folds if it appears before the appearance of mitotic domains. I speculate that this could explain why the CF appears before the mitotic domains in the Drosophila embryo.
n the second project, I study a case of shape change associated with the development of the Drosophila wing. Here I focus on the wing disc pouch, an epithelial monolayer that forms the adult wing blade. During metamorphosis, the larval wing disc evaginates to form the pupal wing. This process is known as eversion. During late larval stage, the wing disc pouch looks like a spherical cap. I refer to this stage as wL3 (wandering larval stage 3) in this thesis. Four hours after pupariation (4hAPF), the spherical cap deforms to an asymmetric dome such that it has a higher curvature along one cross-section compared to its perpendicular cross-section. Using segmented outlines of the wing in the two cross-sections of multiple images at different developmental stages, I compute the mean shape and quantify the curvature along the arclength of these shapes.
To model this shape change, I use a 3D spring lattice whose initial curvature is matched to the curvature of the wL3 stage. Next, using apical cell shape data, provided by my collaborator, I compute a quantity referred to as a “spontaneous deformation tensor”. This tensor quantifies the amount of deformation, at a specific location between two developmental stages, due to cell area changes, cell elongation changes, and neighbour exchanges. I input this deformation pattern in my model which then changes its 3D shape.
I find that the deformation due to changes in cell area and elongation increase the size of the tissue globally without affecting its curvature. However, the deformation due to cell rearrangements enhances curvature along one cross-section more than its perpendicular cross-section.
Overall, the quantifications and modelling shows how different cellular behaviours deform the tissue locally. Moreover, a spatial pattern of different cellular behaviours can explain essential aspects of the shape change observed during the development of the wing.
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The Ron Receptor Tyrosine Kinase in Tissue MorphogenesisMeyer, Sara January 2009 (has links)
No description available.
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Depth Technology: Remediating OrientationReynolds, Peggy E. 18 December 2012 (has links)
No description available.
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β-catenin overexpression within the metanephric mesenchyme causes renal dysplasia via upregulation of the Gdnf signalling axisSarin, Sanjay 04 1900 (has links)
<p>Renal dysplasia, a developmental disorder characterized by defective nephrogenesis and branching morphogenesis, ranks as one of the major causes of renal failure among the pediatric population. The molecular mechanisms underlying the pathogenesis of renal dysplasia are not well understood; however, changes in gene expression are a major contributing factor. In this study, we demonstrate that the levels of activated β-catenin, a transcriptional co-regulator, are elevated in the nuclei of ureteric, stromal, and mesenchymal cells within dysplastic human kidney tissue. To determine the mechanisms by which mesenchymal β-catenin over-expression leads to renal dysplasia, we generated a conditional mouse model in which β-catenin was stabilized exclusively in the metanephric mesenchyme. Kidneys from these mutant mice are remarkably similar to dysplastic human kidneys. In addition, these mutant mice also demonstrate the formation of 4 to 6 ectopic kidneys. While nephrogenesis appeared normal, investigation of ureteric branch pattern revealed ectopic ureteric budding off the Wolffian duct, ectopic branching off the initial ureteric bud stalk and a disorganization of branch patterning. In-situ hybridization of mutant kidneys revealed increased expression of Gdnf, Cret, and Wnt11, key factors that regulate ureteric branch patterning. We further demonstrate that β-catenin directly binds to TCF consensus binding sites within the Gdnf promoter region located 4.9kb, 2.25kb and 2.1kb upstream of the Gdnf transcriptional start site. Molecular cloning of the 4.9kb fragment upstream of a luciferase gene revealed that ß-catenin regulates gene transcription from the 4.9kb consensus site. Consistent with these findings, genetic deletion of β-catenin from the metanephric mesenchyme cell lineage lead to decreased Gdnf expression and a reduction in ureteric branching morphogenesis resulting in renal hypoplasia. Taken together, our findings establish that β-catenin is an essential regulator of Gdnf expression within the metanephric mesenchyme. Furthermore, we have identified a novel disrupted signalling pathway that contributes to the pathogenesis of renal dysplasia. In this pathway, an over-expression of β-catenin directly leads to an over-expression of Gdnf, causing ectopic and disorganized branching morphogenesis and, consequently, renal dysplasia.</p> / Master of Health Sciences (MSc)
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Three-dimensional Surface Changes in the Mandible during Growth and DevelopmentViechnicki, Bryon Joseph January 2011 (has links)
Three-dimensional analysis of mandibular growth provides the potential for pedodontists, orthodontists and surgeons to prescribe treatment that works in harmony with the individual growth of the patient. Despite efforts by 3D pioneers, the visualization of growth and development remains reminiscent of the landmark-based cephalometric analyses used in two-dimensional studies. The objective of this study was to identify 3D topographical changes of the mandible during growth and development of adolescent orthodontic patients. Nine pairs of pre- and post-orthodontic cone-beam computed tomography (CBCT) scans were used to generate mandibular surfaces. Surfaces were superimposed on trabecular bone in the anterior mandible using a mutual information algorithm, and topographical changes were visualized and quantified. The intra- and inter-rater intraclass correlation coefficients for surface generation (0.94 and 0.93, respectively) and superimposition (0.96 and 0.82, respectively) demonstrate the reliability of the techniques. The findings of this study support the theories of bone remodeling reported in histological, implant-based, and landmark studies of mandibular growth. / Oral Biology
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Functional Analysis of the Role of Slit and its Receptors During D. melanogaster Heart MorphogenesisVassilieva, Katerina 12 1900 (has links)
Proper formation of the heart is a critical developmental event which requires strict
regulation of coordinated cardial cell adhesion, alignment, and migration. The simple, tube-like heart of the fruit fly, Drosophila melanogaster, has proven to be an attractive system in which to study the regulatory pathways which control cardiogenesis. This is mainly due to its strikingly similarity to the vertebrate heart during early embryogenesis. In addition, many genes identified in association with congenital heart disease in humans have homologues in Drosophila, suggesting that this model organism has great potential to contribute to cardiovascular research. The extracellular matrix protein encoded by slit is a ligand for the receptors Robo, and Robo2 (lea). Recently, a third receptor for Slit has been identified as the heparin sulfate proteoglycan Syndecan. The main objective of this thesis was to use time lapse confocal imaging in order to develop further understanding of the mechanisms which result in heart assembly defects in slit, robo, lea, and syndecan mutants. We also aimed to gain a better understanding of the role of Syndecan within the Slit-Robo pathway and elucidate its relative contribution to development of the mature heart. In mutants homozygous for slit, as well as mutants doubly heterozygous for robo and lea, cardial cell alignment, adhesion, and synchronized migration were disrupted. The heart phenotype of syndecan homozygous mutants was similar that of slit and robo, lea, however the migration speed of cells to the midline did not seem to be affected. Based on our findings, we hypothesize that Slit may have Syndecan-dependent and Syndecan-independent functions in the heart. / Thesis / Master of Science (MSc)
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Implication des voies de différenciation épithéliale précoce dans la morphogenèse mammaire et la progression des cancers du sein / Involvement of precocious epithelial differentiation pathways in mammary morphogenesis and progression of breast cancers and progression of breast cancersIdoux-Gillet, Ysia 20 September 2013 (has links)
La morphogenèse de la glande mammaire résulte de la coordination de différentes voies, incluant l'apoptose, la prolifération, la différenciation et la dynamique des cellules souches/progénitrices. La transition épithéliale-mésenchymateuse (EMT) semble être impliquée dans ces voies de signalisation. Ainsi, nous nous sommes concentrés sur le facteur de transcription Slug, un gène clé régulant l'EMT, et son implication dans la morphogenèse de la glande mammaire. Dans un premier temps, en utilisant un modèle de souris transgéniques Slug-Lacz, nous avons localisé Slug dans une sous-population couvrant 10 à 20% des cellules basales du tubule et des cap cells du bourgeons terminal, coexprimant les marqueurs P-cadhérine, CK5, CD49f. Ensuite, nous avons montré par des expériences in vitro de perte et de gain de fonction, que Slug régulait la différenciation et la prolifération des cellules épithéliales mammaires. De plus, nous avons trouvé que Slug inhibait l'apoptose, promouvait la motilité cellulaire, et permettait l'émergence et la croissance de mammosphères clonales. Ce dernier point montre l'implication de Slug dans les cellules souches, qui est renforcé par le fait que des cellules primaires déficientes pour Slug étaient incapables de donner des mammosphères secondaires. Par ailleurs, nous avons pu observer in vivo que les souris déficientes pour Slug présentaient un retard de développement de la glande mammaire, possédant moins de cellules en prolifération, et une surexpression des marqueurs des cellules luminale CK8/18, GATA3 et ER. D'autres gènes régulant l'EMT sont retrouvés surexprimés, suggérant un mécanisme de compensation, qui peut expliquer le fait que le retard de développement de la glande mammaire est rattrapé à l'âge adulte. Les glandes mammaires Slug-knockout présentaient également des branchements excessifs, évoquant une différenciation précoce, similaire aux glandes mammaires de souris déficientes pour la P-cadhérine, exprimée dans les cellules basales. Sachant cela, nous avons constaté que la P-cadhérine était diminuée dans les glandes mammaires Slug-knockout, et dans les cellules CommaDβ traitées par siRNA ciblant Slug. Nous avons alors trouvé que Slug se liait directement au promoteur de la P-cadhérine et l'activait, et que cette dernière intervenait dans certains effets fonctionnels de Slug, tels que la croissance de mammosphères, la différenciation et la migration cellulaire. Ainsi, nous avons montré l'importance d'une nouvelle voie de signalisation Slug/P-cadhérine dans les capacités souches/progénitrices des cellules épithéliales mammaires, intégrant la différenciation et la motilité cellulaire, et nous avons maintenant une meilleure compréhension de son rôle dans l'agressivité de certains cancers du sein. / Mammary gland morphogenesis results from the coordination of different pathways, including apoptosis, proliferation, differentiation, and stem/progenitor cell dynamics. Epithelial-mesenchymal transition (EMT) appears to be involved in these signalling pathways. Thus, we focused on transcription factor Slug, a key gene regulating EMT, and its involvement in mammary gland morphogenesis. First, using a Slug–LacZ transgenic mice model, we located Slug in a subpopulation covering about 10–20% basal duct cells and cap cells of terminal end bud, coexpressed with basal markers P-cadherin, CK5 and CD49f. Then, we have shown by in vitro experiments of loss and gain of function that Slug regulated the differentiation and proliferation of mammary epithelial cells. Moreover, we found that Slug inhibited apoptosis, promoted cell motility, and allowed the emergence and growth of clonal mammospheres. This last point shows the involvement of Slug in stem cells, which is reinforced by the fact that primary cells deficient for Slug were unable to give secondary mammospheres. Furthermore, we observed in vivo that mice deficient for Slug showed delayed development of the mammary gland, with less proliferating cells, and overexpression of markers of luminal cells CK8/18, GATA3 and ER. Other genes regulating EMT are found overexpressed, suggesting a compensatory mechanism, which can explain the fact that the delayed development of the mammary gland is caught up in adulthood. The Slug-knockout mammary glands also showed overbranching, evoking an early differentiation, similar to the mammary glands of mice deficient in P-cadherin, expressed in the basal cells. Knowing this, we found that P-cadherin was decreased in Slug-knockout mammary glands, and in CommaDβ cells treated with siRNA targeting Slug. We then found that Slug binds directly to the promoter of the P-cadherin and activated it, and that P-cadherin was involved in some functional effects of Slug, such as mammospheres growth, differentiation and cell migration. Thus, we have shown the importance of a new signalling pathway Slug/P-cadherin in the capacity of mammary epithelial stem/progenitor cells, integrating differentiation and cell motility, and we now have a better understanding of its role in the aggressiveness of some breast cancers.
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