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Suriben, Rowena Mae Obina. „Dact1 functions in the planar cell polarity pathway during vertebrate gastrulation“. Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390079.
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Yates, Laura Louise. „The role of the planar cell polarity pathway in branching morphogenesis“. Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:65200972-a024-4b68-bfd3-a857ec8d99d8.
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The development of organs such as the lung and kidney occurs by branching morphogenesis. Changes in the cytoskeletal architecture, cell-cell adhesion and cell polarity are necessary for the formation of new branches. Interactions and reciprocal signalling between epithelial and mesenchymal cells mediate these organised cell movements that give rise to a complex system of tubes suitable for the transport of gas or fluids. Mutations that disrupt formation of either the correct number, or shape of epithelial branches, affect lung function. This, in turn, can lead to congenital abnormalities such as cystadenomatoid malformations, pulmonary hypertension or lung hypoplasia. Defects in lung architecture are also associated with adult lung disease, particularly in cases of idiopathic lung fibrosis. Identifying the signaling pathways that drive epithelial tube formation will likely shed light on both congenital and adult lung disease. This study shows that mutations in the planar cell polarity (PCP) genes: Celsr1; Vangl2 and Scribble, lead to disrupted lung development and defects in lung architecture. Examination of Vangl2 mutant kidneys reveals similar impairment of branching morphogenesis. Detailed histological and immunocytochemical analysis reveals that lungs from Celsr1Crsh/Crsh, Vangl2Lp/Lp and ScribbleCrc/Crc mice are small and misshapen with fewer branches, and by late gestation exhibit thickened interstitial mesenchyme and defective saccular formation. Moreover, epithelial integrity is disrupted, cytoskeletal remodeling perturbed and mutant endoderm does not branch normally in response to the chemoattractant FGF10. In ex-vivo culture, inhibition of Rho kinase, an important downstream effector of the PCP signaling pathway, can mimic the branching defects observed in these three mouse mutants. Furthermore, all three proteins are present in restricted spatial domains within lung epithelium. ScribbleCrc/Crc lungs, the most severely affected line, exhibit additional defects in components of the tight and adherens junctions; this in turn affects lumen diameter. These findings show that components of the PCP pathway: Celsr1; Vangl2 and Scribble are required for normal foetal lung development, thereby revealing a novel signalling pathway critical for this process. Examination of postnatal mice was not possible as homozygous mutations result in embryonic lethality. However, an assessment of Vangl2Lp/+ mice reveals that loss of a single copy of Vangl2 is enough to cause defects in embryonic lung development that persist into adult life, affecting lung function. Similarly, Vangl2Lp/+ mice show a small but significant reduction in kidney glomeruli.
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Classen, Anne-Kathrin. „Hexagonal packing of Drosophila wing epithelial cells by the Planar Cell Polarity pathway“. Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2006. http://nbn-resolving.de/urn:nbn:de:swb:14-1157034530833-40169.
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The mechanisms that order cellular packing geometry are critical for the functioning of many tissues, but are poorly understood. Here we investigate this problem in the developing wing of Drosophila. The surface of the wing is decorated by hexagonally packed hairs that are uniformly oriented towards the distal wing tip. They are constructed by a hexagonal array of wing epithelial cells. We find that wing epithelial cells are irregularly arranged throughout most of development but become hexagonally packed shortly before hair formation. During the process, individual cell junctions grow and shrink, resulting in local neighbor exchanges. These dynamic changes mediate hexagonal packing and require the efficient delivery of E-cadherin to remodeling junctions; a process that depends on both the large GTPase Dynamin and the function of Rab11 recycling endosomes. We suggest that E-cadherin is actively internalized and recycled as wing epithelial cells pack into a regular hexagonal array. Hexagonal packing furthermore depends on the activity of the Planar Cell Polarity proteins. The Planar Cell Polarity group of proteins coordinates complex and polarized cell behavior in many contexts. No common cell biological mechanism has yet been identified to explain their functions in different tissues. A genetic interaction between Dynamin and the Planar Cell Polarity mutants suggests that the planar cell polarity proteins may modulate Dynamin-dependent trafficking of E-cadherin to enable the dynamic remodeling of junctions. We furthermore show that the Planar Cell Polarity protein Flamingo can recruit the exocyst component Sec5. Sec5 vesicles also co-localizes with E-cadherin and Flamingo. Based on these observations we propose that during the hexagonal repacking of the wing epithelium these proteins polarize the trafficking of E-cadherin-containing exocyst vesicles to remodeling junctions. The work presented in this thesis shows that one of the basic cellular functions of planar cell polarity signaling may be the regulation of dynamic cell adhesion. In doing so, the planar cell polarity pathway mediates the acquisition of a regular packing geometry of Drosophila wing epithelial cells. We identify polarized exocyst-dependent membrane traffic as the first basic cellular mechanism that can explain the role of PCP proteins in different developmental systems.
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Shafer, Jeong Deok Beth. „Planar cell polarity pathway and axon guidance in the developing spinal cord“. Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3397199.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed March 23, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 95-105).
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Godfrey, Grayland W. II. „Characterizing the Role of Key Planar Cell Polarity Pathway Components in Axon Guidance“. VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4841.
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An essential process to the development of the neural network of the nervous system is axon guidance. The noncanonical Wnt/Planar Cell Polarity pathway has been identified as an integral component in controlling the projection of axons during axon guidance. Prickle, ROR1 and ROR2 are PCP related proteins that do not have clearly defined roles in the process. This study aims to use zebrafish CoPA neurons as a model to study the roles of Prickle, ROR1, and ROR2 in axon guidance. Using in situ hybridization, morpholino knockdown, and CRISPR/Cas9 loss of function experiments were able to identify ror1, ror2 and prickle as potential required components in CoPA neuron axon guidance. Elucidating the role of these protein in axon guidance not only will increase our knowledge of the PCP pathway but it will also increase our understanding of the development of the nervous system.
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Watson, Julia Alice. „Investigating the role of Wnt/Planar cell polarity (PCP) in Neuromesodermal Progenitors (NMPs)“. Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31193.
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Neuromesodermal progenitors (NMPs) are bipotent progenitors, located at the caudal end of the embryo and are essential for axis formation. These stem cell-like progenitors possess the ability to self-renew and differentiate to both mesodermal and neural lineages, such as skeletal muscle and spinal cord derivatives. These progenitors arise at E8.5 and are localised in the caudal lateral epiblast (CLE), a posterior region of the embryo near the primitive streak. Later in development, they reside in the tail bud until cessation of axial elongation at E13.5. Throughout these stages NMPs are characteristically marked by co-expression of T(Bra) (Brachyury) and Sox2. This characteristic is also present in in vitro NMPs, which can be derived from Epiblast Stem Cells (EpiSCs) through treatment with Wnt/β-catenin signalling agonists and Fgf2, which simulates their in vivo environment. Protein and mRNA profiling of NMPs and mutant phenotypes in vivo supports the hypothesis that a non-canonical Wnt pathway, the Wnt/Planar Cell Polarity pathway (PCP) could be involved in NMP fate decision and/or maintenance. This thesis focuses on understanding more about the role of PCP by aiming to identify the spatio-temporal profile of Wnt/PCP pathway components in NMP regions during axial elongation, as well as determining its role in NMP behaviour through manipulation of this pathway via in vivo and in vitro assays Employing in situ hybridisation and immunohistochemistry techniques, key Wnt/PCP components, including Pk1, Vangl2 and Ptk7, were confirmed to be present in in vivo and in vitro NMPs, thus, providing strong evidence that Wnt/PCP may be involved regulating NMP behaviour. Disruption of Wnt/PCP signalling through overexpression of Wnt/PCP components was tested in refined in vivo and in vitro assays. Overexpression of Vangl2 and Ptk7, but not Pk1 in NMPs regions in vivo resulted in loss of contribution to neural lineages, as well as lower contribution to NMP regions themselves. Similarly, Wnt/PCP components were disrupted in vitro through generation of dox-inducible overexpression cells lines for Wnt/PCP components. These lines were used to generate NMPs from an optimised novel alternative source Epiblast-Like Cells (EpiLCs), however no clear affect to lineage was observed. Overall this work has successfully advanced our knowledge of Wnt/PCP mediated control of NMP differentiation and maintenance, and provided a finer grained description of the relationships between them.
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Freeman, Emily. „Crosstalk Between the Planar Cell Polarity and Hedgehog Signaling Pathways Influences Satellite Cell Fate“. Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38707.
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Our laboratory has identified two secreted proteins, Wnt7a and Sonic hedgehog (Shh), that regulate satellite cell (SC) fate, during muscle differentiation. While Wnt7a stimulates symmetric SC division through the planar cell polarity (PCP) pathway, Shh activates Myf5 expression in the committed SC following asymmetric division through cilia-mediated Hedgehog (Hh) signaling. Crosstalk between these pathways has been well characterized during development, and is likely to be conserved in muscle regeneration. Indeed, accumulating evidence suggests the PCP pathway influences primary cilia formation, an organelle required for proper Hh signal transduction. Here we show that Wnt7a treatment in primary myoblasts increases the presence of primary cilia. Additionally, using myofiber culture, we demonstrate that Wnt7a increases myogenin (MyoG) expression. Removal of primary cilia through a small interfering RNA (siRNA) targeted towards IFT88 impedes Wnt7a mediated MyoG expression, suggesting crosstalk between the PCP and Hh pathways facilitates muscle differentiation. Furthermore, through siRNA knockdown we have identified the downstream PCP effectors, Inturned and Fuzzy as the main candidates responsible for this crosstalk. Knockdown of either Inturned or Fuzzy impedes Wnt7a-mediated MyoG expression. Taken together our data demonstrates crosstalk between the PCP pathway and Hh signaling regulates the differentiation of SCs.
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Oteiza, Alvarez Pablo. „Role of the Planar Cell Polarity Pathway in the Morphogenesis of the Laterality Organ in Zebrafish“. Tesis, Universidad de Chile, 2009. http://www.repositorio.uchile.cl/handle/2250/110540.
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A pesar de su aparente simetría bilateral, el plan corporal de los vertebrados presenta consitentes asimetrías en localización, estructura y función de diversos órganos internos como el corazón, los intestinos y el cerebro. Los mecanismos mediante los cuales el eje izquierda-derecha se establece durante el desarrollo embrionario han evolucionado desde arreglamientos cito esqueléticos y flujos iónicos tempranos hacia la actividad de estructuras ciliadas transigentes. Se ha propuesto que la actividad de los cilios en estas estructuras (denominadas órganos de lateralidad) genera un flujo extracelular de morfógenos hacia la izquierda de la línea media (el flujo Nodal), el cual determina la lateralidad de cascadas de expresión génica asimétrica y, como consecuencia, de organogénesis asimétrica (revisado en Hamada y cols., 2002; Hirokawa y cols., 2006; Raya e Izpisúa-Belmonte, 2006). Aunque la presencia de estos órganos de lateralidad se encuentra conservada en vertebrados incluyendo mamíferos (Nonaka y cols., 1998; Okada y cols., 2005), anfibios (Schweickert y cols., 2006) y peces teleósteos (Essner y cols., 2005; Okada y cols., 2005), tanto el orígen embrionario como los mecanismos mediante los cuales las células ciliadas se organizan en una estructura capaz de inducir un flujo nodal hacia la izquierda son prácticamente desconocidos. En el pez cebra, los precursores de las células ciliadas son un grupo de aproximadamente 20-30 células denominadas Dorsal Forerunner Cells (DFCs). Las DFCs no involucionan sino que migran por delante del blastodermo dorsal durante la gastrulación para dar origen a principios de la somitogénesis a la vesicula de Kupffer (KV), una estructura epithelial ciliada en la cual se genera el flujo nodal del pez cebra (Cooper y D’amico, 1996; Essner y cols., 2005). En esta tesis, hemos utilizado microscopía confocal y de 2-fotones en tiempo extendido para analizar a nivel de célula única el origen, migración y organogénesis de las DFCs. Nuestros resultados demuestran que, inesperadamente, las DFCs se originan de la capa epitelial extraembrionaria del pez cebra. Nuestros análisis muestran que células epiteliales dorsales (Dorsal Epithelial Cells ó DSE) ingresan previo a la gastrulación en un proceso dependiente de la vía de señalización de Nodal/TGF y son cubiertas por las células vecinas de la capa epitelial envolvente (la Enveloping Layer ó EVL) dando origen a las DFCs. Las DFCs entonces se polarizan hacia la EVL y se unen a ella migrando en estrecho contacto con el epitelio externo durante la epibolía. A medida que la epibolía continúa, las DFCs se organizan en sus puntos de contacto con la EVL formando estructuras epiteliales con forma de roseta, las cuales son internalizadas cuando las DFCs y la EVL se separan a fines de la gastrulación. A comienzos de la somitogénesis, estas rosetas internalizadas abren sus puntos centrales y coalescen en una estructura única a partir de la cual el lumen de la KV aparece y se expande. Al mismo tiempo, la zona apical de las rosetas desarrolla cilios mótiles que generan un flujo Nodal contra las manecillas del reloj. Nuestros resultados además demuestran que wnt11 (Heisenberg y cols., 2000) y prickle 1a (Veeman y cols., 2003; Carreira-Barbosa y cols., 2003), dos components de la vía de señalización no canónica de Wnt o de polaridad celular planar (PCP) participan cooperativamente en la organogénesis de la KV mediante la regulación de la cohesion tisular de las DFCs. En embriones con pérdida de función de wnt11/pk1a, las DFCs aparecen como un grupo celular menos compacto, las rosetas epiteliales fallan en coalescer y aparecen claros defectos morfológicos en el lumen de la KV, los cuales van desde una drástica reducción en su volumen hasta una severa fragmentación. Además, los cilios presentan una fuerte reducción en su longitud, lo que impide la inducción de un flujo nodal efectivo. Estos defectos llevan finalmente a una distribución aleatoria de la expresión génica de Nodal y a una lateralidad randomizada de los órganos internos. Con la finalidad de comprender los mecanismos mediante los cuales la vía de Wnt/PCP controla la cohesión del grupo de DFCs, procedimos a medir mediante microscopía de fuerza atómica (AFM) las fuerzas de adhesión entre DFCs aisladas de embriones con pérdida de función de wnt11/pk1a. Nuestras mediciones indican que la pérdida de función de la vía de Wnt/PCP induce una marcada reducción en las propiedades de adhesión célula-célula de las DFCs. Además, los defectos en la KV ocasionados por la pérdida de función de wnt11/pk1a pueden ser fenocopiados por la pérdida de función de la molécula de adhesión E-cadherina específicamente en las DFCs. En su conjunto, los resultados de la presente tesis entregan novedosos datos sobre el orígen y las transformaciones morfogenéticas que llevan a la formación de la KV, el órgano de lateralidad del pez cebra; y revelan un rol fundamental de la cohesión tisular mediada por la vía de Wnt/PCP en la coordinación de este proceso.
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Tanner, Raymond. „A Role for the Planar Cell Polarity Pathway in Neuronal Positioning Along the AP Axis of C. elegans“. Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31521.
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We sought to investigate the role of the Planar Cell Polarity (PCP) pathway in neuronal positioning along the Anterior-Posterior (AP) axis of C. elegans, and chose the worm’s DD-type motor neurons as a model. The six DD neurons (DD1-DD6) are evenly spaced in the ventral nerve cord of wild type animals. Here we showed that mutations in core PCP genes caused DD neuron spacing and positioning defects. prkl-1 double mutant combinations with vang-1 and fmi-1 showed a suppression of the more severe prkl-1 single mutant defects, which was evidence of genetic interactions between these PCP components. We also conducted a candidate screen of Frizzled, Dishevelled, Wnt, and ROCK genes, and found that dsh-1/Dishevelled, mom-2/Wnt and let-502/ROCK also played roles in DD neuronal positioning. Both vang-1 and prkl-1 were found to function within the nervous system to guide DD neuronal positioning, and prkl-1 was further identified as playing a cell autonomous role. The origins of observed DD neuron anterior positioning defects were investigated during embryogenesis, in which 1.5 fold stage prkl-1(ok3182) embryos displayed delayed intercalation of the DD neurons. This represents a novel role for the PCP pathway in mediating DD neuronal intercalation.
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Sasselli, V. „The potential role of Rac signalling and the planar cell polarity pathway in wiring of the enteric nervous system“. Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318135/.
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The functional development of the enteric nervous system (ENS) requires newly generated neurons and their progenitors to migrate to their appropriate sites, extend neurites, guide axons and dendrites to suitable locations and establish synaptic connections with the appropriate targets. Very little is known about the molecular mechanism underlying these processes. Recent studies have suggested a potential role of Rho GTPases as intracellular regulators of several ENS developmental processes. However, the relative participation of specific members of the family in migration, neurogenesis and axonal guidance of enteric progenitors has not been addressed yet. Here, we investigate the in vivo role and genetic interaction of two members of the Rho-GTPase family, Rac1 and Rac3 in enteric neurogenesis. Taking advantage of the Cre/loxP recombination system and a Rac1 conditional inactivation mouse strain (Rac1flox/flox), we generated a Sox10Cre; Rac1flox/flox;R26ReYFP mouse line, where Rac1 gene is specifically ablated in the neural crest population which is also labeled by the expression of Yellow Fluorescent Protein. Secondly, we generated double Rac1;Rac3 mutant animals by crossing the Sox10Cre;Rac1flox;R26ReYFP mouse line to a constitutive Rac3 KO strain (Rac3-/-). In vivo and in vitro studies on Rac-deficient enteric neural crest cells and neurons showed distinctive roles for Rac1 and Rac3 in migration of enteric neural crest cells (ENCCs), in development of enteric neurons and in control of cell polarity within the developing ENS. In addition, we also undertook a candidate gene approach to investigate the involvement of Wnt-signaling genes in enteric axon guidance and circuit formation. We found that two of the core components of the Planar Cell Polarity pathway, the Wnt receptor Frizzled 3 (Fzd3) and the Cadherin EGF LAG seven-pass G-type receptor 3 (Celsr3) are expressed specifically in ENCCs during embryonic development. Here we show, by using a combination of in vivo approaches that in mice deficient in either protein, enteric neurons had characteristic defects in neuronal tract formation and in patterning of individual axonal projections evident from early stages of ENS development. Furthermore, preliminary data show that these specific defects in ENS wiring might be the cause of impaired intestinal function and, therefore, provide the basis for understanding the aetiopathology of several idiopathic enteric neuropathies in humans.
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Barrott, Jared James. „Wnt5a Signaling Independently of the Planar Cell Polarity Pathway Resulting in Convergent Extension and Neural Tube Closure During Vertebrate Development“. Diss., CLICK HERE for online access, 2008. http://contentdm.lib.byu.edu/ETD/image/etd2612.pdf.
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Wu, Mingfu. „A novel non-canonical WNT pathway regulates the asymmetric b cell division in Caenorhabditis elegans“. Diss., Kansas State University, 2005. http://hdl.handle.net/2097/355.
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Doctor of PhilosophyDepartment of Biology
Michael A. Herman
The polarities of several cells that divide asymmetrically during C. elegans development are controlled by Wnt signaling. LIN-44/Wnt and LIN-17/Fz control the polarities of cells in the tail of developing C. elegans larvae, including the male-specific blast cell, B, which divides asymmetrically to generate a larger anterior daughter and a smaller posterior daughter. We determined that the canonical Wnt pathway components are not involved in the control of B cell polarity. However, POP-1/Tcf is involved and asymmetrically distributed to B daughter nuclei. Aspects of the B cell division are reminiscent of the divisions controlled by the planar cell polarity (PCP) pathway that has been described in both Drosophila and vertebrate systems. We identified C. elegans homologs of Wnt/PCP components and have determined that many of them appear to be involved in the regulation of B cell polarity and POP-1 asymmetric distribution to B daughter nuclei. Thus a non-canonical Wnt pathway, which is different from other Wnt pathways in C. elegans, but similar to the PCP pathways, appears to regulate B cell polarity. Molecular mechanisms of this PCP pathway were also investigated. We determined that LIN-17/Fz is asymmetrically distributed to the B cell cortex prior to, during, and after, division. Furthermore, the asymmetric localization of LIN-17::GFP is controlled by LIN-44/Wnt and MIG-5/Dsh. The cysteine rich domain (CRD), seven trans-membrane domain and KTXXXW motif of LIN-17 are required for LIN-17 to rescue lin-17, while only seven trans-membrane domains and KTXXXW motif are required for LIN-17 asymmetric localization. MIG-5::GFP asymmetrically localized to the B cell prior to and after division in a LIN-17/Fz dependent manner. We examined the functions of these MIG-5 domains. The DEP domain is required for MIG-5 membrane association, while the PDZ domain is responsible for different levels of MIG-5 in the B daughters. The DEP and PDZ domain are required to rescue B cell polarity defect of mig-5 males, while the DIX domain is not that important. In summary, a novel PCP-like pathway, in which LIN-17 and MIG-5 are asymmetrically localized, is conserved in C. elegans and involved in the regulation of B cell polarity.
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Schenkelaars, Quentin. „Origine et évolution des voies Wnt chez les métazoaires : étude comparée de diverses espèces d'éponges“. Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4014.
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Les éponges (Porifera) sont l'une des premières lignées d'animaux à avoir émergé. De ce fait, elles sont considérées comme des espèces clés pour retracer l’origine et l'évolution des gènes et des voies de signalisation qui ont sous-tendu l'apparition de la pluricellularité chez les métazoaires. Entre autres, les voies Wnt ont été décrites comme des cascades génétiques essentielles du control de nombreux mécanismes cellulaires (prolifération, communication, adhésion, motilité, etc.) au cours du développement précoce des bilatériens et des cnidaires. C’est pourquoi, l'étude de ces voies, chez les lignées d’émergences plus anciennes sont essentielles afin de comprendre l'origine des plans d’organisation des animaux.J’ai alors entrepris de nombreuses analyses bioinformatiques sur différentes bases de données d’éponges. Il apparait alors que l’ancêtre commun des éponges possédait déjà certainement tous les composants des voies Wnt. Néanmoins, à ce jour, puisque l’intégralité de ces composants n’a été identifiée que dans le genre Oscarella (lignée des Homoscleromorpha), différentes pertes secondaires sembleraient s’être produites chez les démosponges, les éponges calcaires et les hexactinellides. Afin de tester si ces gènes orthologues sont impliqués dans la mise en place du plan d’organisation des éponges, des études fonctionnelles ont été mises en œuvre. Ces approches fonctionnelles réalisées sur deux lignées d’éponges différentes tendent alors à confirmer la conservation des voies de signalisation Wnt dans les processus de mise en place des plans d’organisation des animaux, à la fois au cours de l'embryogenèse mais aussi lors du renouvellement cellulaire chez l'adulteSponges (Porifera) are one of the earliest emerged animal lineages. They are thus considered as key species to retrace early evolution of genes and pathways underlying the emergence of multicellularity in metazoans. Among others, the Wnt pathways have been described as crucial modules controlling cell proliferation, cell communication, cell adhesion and cell motility during the early development of Bilaterians and Cnidarians. Therefore the study of these signaling pathways in more basally branching lineages is essential for unraveling the origin of animal body plans. I performed numerous bioinformatic analyses on different poriferan databases. One of my main results is that the last common ancestor of Porifera probably already possessed all the components of the Wnt pathways. Nevertheless, because, to date, all these components were only retrieved in the Oscarella genus (Homoscleromorpha lineage), several secondary gene losses would have occurred in other sponge lineages, namely Demospongia, Calcarea and Hexactinellida.In order to test whether or not these retrieved orthologous genes, are involved in patterning sponge body plan (as they do in Bilateria and Cnidaria), functional studies were implemented. These functional studies performed on two different lineages tend to confirm that Wnt signaling pathways were conserved from sponges to vertebrates to pattern animal body plan during both embryogenesis and cell renewal in adult
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Darby, Daniel. „A mechanism of oriented cell division underlying cardiac chamber expansion“. Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS666.
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La morphogenèse est un processus qui nécessite une régulation à plusieurs niveaux à la fois physique et génétique. Les perturbations de ce programme dans le contexte du cœur ont souvent des conséquences importantes sur l'organe, comme le prouve l’incidence de 1% des cardiopathies congénitales à la naissance. Les cardiopathies congénitales telles que les cardiomyopathies, affectent l’architecture du muscle cardiaque essentielle à sa fonction contractile. Les parois ventriculaires sont particulièrement importantes, à la fois pour définir la taille des lumières ventriculaires et pour établir une architecture de myofibre orientée, renforçant l’efficacité de la contraction. Des travaux antérieurs dans le laboratoire ont permis de mettre en évidence l’émergence de l’orientation du myocarde. L'analyse clonale a révélé que la croissance tissulaire orientée corrélait avec l'expansion des ventricules (Sigolène M. Meilhac et al., 2004) et préfigurait l’architecture des myofibres du cœur nouveau-né (Meilhac et al., 2003). L'analyse de l’architecture cellulaire a révélé une coordination locale des divisions cellulaires indiquant une orientation des divisions cellulaires (Le Garrec et al., 2013). Ces études suggèrent que la division cellulaire orientée joue un rôle important dans la formation du cœur. Cependant, les mécanismes par lesquels cela est régulé doivent encore être identifiés dans les ventricules embryonnaires. Dans ce projet, nous utilisons une combinaison d'approches transcriptomique, segmentation cellulaire 3D, traitements chimiques en culture d'embryons et interférence moléculaire pour, étudier un mécanisme de division cellulaire orientée. Par séquençage ARN des ventricules, nous avons identifié l’expression de composants de l’appareil NuMA: GPSM, de la voie de la polarité cellulaire planaire et de la voie de mécano-détection des intégrines, qui sont des voies candidates pour réguler l’orientation de la division cellulaire. En parallèle, nous avons voulu déterminer si les cellules des ventricules en expansion se comportaient conformément à la règle de Hertwig. Pour ce faire, nous avons mis en place une méthode d’imagerie de l’architecture cellulaire dans le cœur entier par transparisation CUBIC et microscopie tridimensionnelle à feuille de lumière. Nous avons également amorcé le développement d’une méthode automatique de segmentation pour quantifier les axes de division cellulaire dans les ventricules. En comparant l’axe d'élongation des cellules aux axes de division les outils et les approches décrite ci-dessus permettront de conclure s'il existe une coordination entre les deux. Pour analyser l'importance des contractions cardiaques sur la croissance orientée des ventricules, nous avons établi des conditions de culture d'embryons traités avec des perturbateurs pharmaceutiques de la contraction cardiaque. Les résultats préliminaires indiquent qu'une augmentation et une diminution du taux de contraction affectent la forme du cœur. Enfin, nous avons conçu des vecteurs pour cibler les trois voies mentionnées ci-dessus avec des protéines dominant négatives. Les résultats de cette recherche pourraient avoir des applications en ingénierie tissulaire pour la réparation du cœurThe development of the heart is an intricate process both physically and genetically which requires regulation on many levels. Perturbations of this cardiogenic programme often has potent consequence on the organ and this is evident from the 1% incidence in births which are affected by a congenital heart disease (CHD). CHDs, such as cardiomyopathies, affect the architecture of the cardiac muscle, which is vital to the heartsfunction. The shape of the ventricular walls is particularly important to their function in terms of both defining the shape of the ventricular chambers and in establishing an appropriate myofiber architecture for efficient contractions (Meilhac et al., 2003). Previous work in the lab has provided insight into how this is achieved in the ventricles. It was found, through clonal analysis, that oriented tissue growth underlies cardiac chamber expansion (Meilhac et al., 2004). Analysis of earlier stages of the embryonic heart found regional coordination of cell divisions which preconfigured the myofiber architecture of the adult heart (Le Garrec et al., 2013). These studies suggest that oriented cell division plays an important role in sculpting the heart. However a mechanism by which this is regulated has yet to be established in the expanding ventricular chambers. In this project we use a combination of transcriptomic analysis, 3D cell segmentation, embryo culture experiments and molecular interference to investigate a mechanism for oriented cell division. Using bulk RNAseq we identified the NuMA:GPSM apparatus, the Planar Cell Polarity pathway and the integrin mechano-sensing pathway as candidates for further analysis. In combination with the transcriptomic analysis we wanted to identify if cells in the expanding ventricles were behaving according to Hertwig’s rule. To do this we have established CUBIC clearing and three dimensional lightsheet microscopy along with an automatic cell segmentation method to quantify cell elongations in the cardiac chambers. By comparing the elongation ratio of the cell to the detected axes of division the tools and approaches described above will enable us to identify if coordination existed between the two and if this was regionally specific. To analyse the impact of cardiac contractions on oriented cell division we established embryo culture experiment conditions paired with pharmaceutical interference of contractions. Preliminary results indicate that both an increase and decrease of contraction rate affects the shape of the heart. Finally, we will target the three pathways mentioned above with dominant negative proteins in chimeric hearts to dissect the molecular pathways. The outcome of this research will have potential applications in tissue engineering therapies targeting the heart
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Sun, Simon. „Planar Cell Polarity and Neurodevelopment“. VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3414.
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Planar cell polarity (PCP) is a developmental signaling mechanism that establishes a polarity within the plane of an epithelium. PCP has been shown to play a role in guiding numerous neurodevelopmental processes such as convergent extension, neuron migration, and axon pathfinding. Certain commissural neurons in the dorsal spinal cord make a series of guidance decisions en route to the brain: first, a ventral projection along the D-V axis, followed by a midline crossing, and after exiting the floorplate, a dorso-anterior turn along the A-P axis. Here, we provide in vivo evidence that the axons of the Commissural Primary Ascending (CoPAs) neurons in zebrafish require the PCP genes fzd3a, vangl2, and scribble for rostral pathfinding both before and after crossing the midline. Dorsoventral guidance of CoPA axons is unaltered in fzd3a, vangl2, and scribble mutants, suggesting that the PCP signaling pathway only controls A-P guidance of CoPAs. Our results have provided evidence for two potential non- mutually exclusive models: (i) A-P axon guidance is achieved by cell-autonomous Wnt-Frizzled signaling or that (ii) A-P axon guidance is achieved by non-cell-autonomous PCP signaling in the neuroepithelial environment. The single-cell nature of the CoPA axon system allows for simple genetic manipulation and visualization, which will potentially elucidate the validity of either model. Scribble (Scrib), a member of the LAP family, plays a critical role in establishing and regulating cell polarization in epithelia and during cell migration. In zebrafish, Scrib mutants have defects in convergent extension (CE) cell movements and facial branchiomotor neuron (FBMN) migration. Despite our understanding of Scrib’s genetic role in neurodevelopment, little is known about the subcellular localization of endogenous Scrib in vivo during CE and FBMN migration. We have generated a monoclonal antibody against the C-terminus of zebrafish Scrib and have shown that this antibody is specific against endogenous Scrib in both western blot and immunocytochemical applications. Confocal microscopy of Scrib immunocytochemistry shows that at various developmental stages, Scrib distinctly localizes to basolateral membranes of non polarized epithelium, to the membrane in mesodermal cells undergoing CE, and to the membrane of migrating FBMNs. Furthermore, the distribution of Scrib puncta along membranes of FBMN- FBMN contact is significantly altered in the PCP mutant pk1b. Further application of our newly generated Scrib antibody will potentially lead to new insight on Scrib’s role in neurodevelopment.
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Schamberg, Sabine. „Modelling planar cell polarity in Drosophila melanogaster“. Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/12838/.
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During development, polarity is a common feature of many cell types. One example is the polarisation of whole fields of epithelial cells within the plane of the epithelium, a phenomenon called planar cell polarity (PCP). It is widespread in nature and plays important roles in development and physiology. Prominent examples include the epithelial cells of external structures of insects like the fruit fly Drosophila melanogaster, polarised tissue morphogenesis in vertebrates and sensory hair cells in the vertebrate ear. In this work we focus on the wing and the abdomen of Drosophila, where PCP becomes obvious in the alignment of hairs and bristles. The underlying dynamics are not fully understood yet, but two distinct protein networks centred around the transmembrane proteins Frizzled and Dachsous, respectively, have been shown to play essential roles. We will present and analyse five models for different aspects of the process of planar cell polarisation. The first two models assess the nature of PCP in a generic setting, ensuring that the results are valid for whole classes of PCP models. Models three and four are existing more complex models that include detailed assumptions about the underlying protein interactions of the Frizzled system in the Drosophila wing. Model five considers the Dachsous system in the Drosophila abdomen. We describe the features of the different types of mechanisms and determine the conditions under which they can yield polarity. All five models can establish wild-type polarity for a wide range of parameter values. We find, however, that for model one, three and four an inhomogeneous pattern exists for the same parameter values as the polarised state. Therefore, in these cases either specific initial conditions, which are unlikely in nature, or a global bias are necessary to ensure correct polarisation. Furthermore, we present the effects of clonal clusters of cells on the polarity of the surrounding cells in our models and relate them to the phenotypes observed in experiments. Model one and five show the largest discrepance between the numerical and the experimental results. We discuss the biological relevance of these findings and indicate outstanding questions.
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Harumoto, Toshiyuki. „Regulation of Noncentrosomal Microtubules in Planar Cell Polarity“. 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142444.
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Brzoska, H. L. „Planar cell polarity in kidney development and disease“. Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1558749/.
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Planar cell polarity (PCP) is a signalling pathway regulating epithelial cell alignment and coordinated organisation, processes that are essential for the development and maintenance of healthy organs and tissues. In this thesis, I hypothesised that the core PCP protein, Celsr1 is essential for normal kidney development. Furthermore, I predicted that PCP proteins would be disrupted in a model of renal disease induced by folic acid. Kidneys of mice homozygous for a mutation in Celsr1 (Celsr1Crsh/Crsh) were significantly smaller compared with wild-type littermates and contained a reduced number of ureteric bud tips as assessed by optical projection tomography at embryonic day (E)13.5. The size of the bud tips and the angle at which they branched were unchanged. At E17.5, orientation of mitotic chromosomes was significantly disrupted in Celsr1Crsh/Crsh mutants compared with wild-type embryos. There was an occasional dilatation of proximal tubules and Bowman’s capsules surrounding the glomeruli, but not an overtly-cystic phenotype. I also examined whether Celsr1 interacted with another PCP component, Vangl2 in kidney development. I found that E13.5 Celsr1Crsh/+:Vangl2Lp/+ double heterozygous kidneys were also smaller compared with wild type littermates and had a significantly reduced UB tip number. At E17.5, a loss of corticomedullary differentiation with very few fully developed glomeruli and a disrupted mitotic orientation were observed in Celsr1Crsh/+:Vangl2Lp/+ kidneys compared with wild type littermates. During kidney injury induced by folic acid, a reduction in levels of Celsr1, normally expressed on the apical surface of proximal tubules, was seen in both the acute and fibrotic phases of this model. This data highlights that Celsr1 and the interaction between Celsr1 and Vangl2 are critical for normal kidney development and PCP proteins have a potential role in the progression of renal disease.
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Purdy, Ashley Morgan. „Roles of Planar Cell Polarity Proteins in CoPA Axon Pathfinding“. VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4289.
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In zebrafish, CoPA (Commissural Primary Ascending) is the first among ascending commissural axons to pathfind anteriorly and form the spinal commissure. One pathway that guides their anterior growth is the planar cell polarity (PCP) signaling pathway, but it is not fully known how PCP signaling regulates anterior guidance. We examined CoPA pathfinding in various PCP mutants to determine if anterior-posterior (A-P) guidance of CoPAs is dependent on PCP signaling. We found that certain PCP mutants exhibited anterior pathfinding defects, with approximately half of all affected CoPAs migrating incorrectly posteriorly. By using a translation-blocking DCC (Deleted in Colorectal Cancer) morpholino to prevent CoPA midline crossing, we discovered that CoPA axons in Fzd3a and Scribble mutants show severe defects in A-P guidance, which suggest that PCP influences A-P guidance of CoPAs prior to and after midline crossing.
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Barbosa, Filipa Carreira de Avelar. „Regulation of gastrulation movements by planar cell polarity genes in zebrafish“. Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444345/.
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During vertebrate gastrulation, mesodermal and ectodermal cells undergo convergent extension (CE), a process characterised by cellular rearrangements in which polarised cells intercalate along the medio-lateral axis leading to elongation of the antero-posterior axis. This thesis aims to prove that genes which have been implicated in the establishment of planar cell polarity (PCP) in Drosophila are conserved in the non-canonical Wnt pathway that regulates CE in zebrafish during gastrulation. Firstly, I analyzed functions of Wnt5 and Wnt 11 ligands and of Fz2 and Fz7 receptors in regulating CE movements. Here, I will show that pipetail (ppt/wnt5) mutant is required for regulating CE movements in posterior mesendoderm and ectoderm while its function in the anterior mesendoderm is redundant to siberblick (slb/wntl 1). Based on gene expression analyses, loss of function and gain of function analyzes, the interaction between these Wnt ligands and Fz receptors is dependent on time, concentration and position of expression during gastrulation. Secondly, I will describe the isolation and functional characterisation of the zebrafish homologue of Drosophila prickle (pkl) during gastrulation. Zebrafish pkl functions together with Sib/Wnt 11 and Ppt/Wnt5 to regulate CE movements due to abrogation of Pkl function by morpholino that leads to defective CE movements, enhances the slb/wntl 1 and ppt/wnt5 phenotypes and suppresses the ability of wnt 11 to rescue the sib phenotype. Gain-of- function of Pkl also inhibits CE movements. Additionally, I found that Pkl could destabilise Dsh and thereby block the ability of Fz to target Dsh to the cell membrane by down-regulating levels of Dsh protein. These results suggest that Pkl acts in the non- canonical Wnt pathway to regulate CE, but it is unlikely to be a simply linear component of this pathway. I will describe the isolation of zebrafish flamingo (fmi) genes and characterise the expression pattern during gastrulation. I also describe functional characterisation of those genes during gastrulation. Initially, abrogation of Fmi function by morpholino leads to weakly defective CE movements enhances the slb/wntl 1 phenotype and defective epiboly phenotypes of the offroad (ord)/fmil mutants. In contrast, a dominant negative approach with a mutant form of Fmi, led me to conclude that Fmi is involved in the regulation of CE movements. Together with analyses of Fmi protein, I will discuss how Fmi regulates different gastrulation movements, such as convergent extension and epiboly.
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Lin, Yung-Yao Steven. „Functional analysis of Prickle isoforms in planar cell polarity in Drosophila“. Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614719.
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Tsuji, Takuya. „Long-term preservation of planar cell polarity in reversed tracheal epithelium“. Kyoto University, 2018. http://hdl.handle.net/2433/232475.
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Mei, Xue. „Wnt/planar cell polarity mechanisms in epilepsy and interactions with ciliopathy“. Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/4695.
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The Wnt signaling network has critical roles in embryonic development and is implicated in human disease. One of the outputs of the Wnt network, called the planar cell polarity (PCP) pathway, regulates tissue polarity and directs cell migration. Core PCP components (Frizzled, Dishevelled, Prickle, Vangl, Celsr) localize asymmetrically in polarized cells and establish polarity across the tissue through protein interactions between adjacent cells. The core PCP component activate tissue-specific "effectors" which translate the signal into morphological changes. PCP is related to several disease conditions, including neural tube defects, cystic kidney disease, and cance metastasis. However, mechanisms of the PCP underlying physiological and disease-related conditions are not well understood. Here, I explore functions of the core PCP component Pk, and its relationship to disease, in the zebrafish model system.
Mutations in Pk1 and Pk2 have been identified in human progressive myoclonic epilepsy patients. Pk coodinate cell movement, neuronal migration and axonal outgrowth during embryonic development. Yet, how dysfunctions of pk relates to epilepsy is unknown. Here, I show that knockdown of pk1a sensitizes the zebrafish larva to convulsant drug. To model the defects in central nervous system, I examine neurogenesis in the retina and find that both pk1a and pk2 are required for proper dendritic outgrowth in the retinal inner plexiform layer. Furthermore, I characterize the epilepsy-related mutant forms of Pk1a and Pk2. The mutant Pk1a forms show reduced ability to suppress the retinal neurogenesis defects compared to the wild-type, as well as differential ubiquitination levels. Pk2 mutant forms also show differential activities in overexpression assays and seemingly more stable proteins relative to the wild-type. Taken together, pk1a and pk2 may contribute to epilepsy by affecting neuronal patterning and thus signal processing.
Another aspect of PCP function has been implicated in cilia and cilia-related disorders, also called ciliopathy. PCP effectors have been shown to modulate ciliogenesis and core PCP proteins (Vang and Dvl) regulate cilia orientation. On the other hand, cilia are not required for PCP signaling, especially asymmetric core PCP protein localization. These findings leave open the question what is the precise relationship between PCP and cilia. The Bardet Biedl Syndrome (BBS) is a type of ciliopathy that leads to obesity, retinitis pigmentosa, polydactyly, mental retardation and other symptons. A subset of BBS genes share similar knockdown phenotype in cell migration as seen in PCP knockdown embryos. Shared pehnotypes have led some to proposethat PCP and bbs genes may interact. Yet a direct relationship has yet to be established. I examine the interaction between pk2 and a central Bbs gene, bbs7. By analyzing shared phenotypes in double knockdown embryos, I find no synergistic interaction between the two, suggesting they act in distinct pathways. Bbs regulate ciliary trafficking and in zebrafish, knockdown of bbs genes leads to delayed retrograde melanosome transport. Interestingly, I find knockdown of pk2 suppresses this retrograde transport delay. Additionally, pk2 knockdown embryos show a delay in anterograde melanosome transport. These findings highlight a new role for pk2 in intracellular transport and clarifies the relationship between PCP and BBS.
In summary, my work here strengthens the link between pk mutations and human epilepsy and identifies functions of pk in retinal neurogenesis and in intracellular transport. To what extent the role of neurogenesis and intracellular transport are related is worth future study. Yet, this new information provides insights into potential mechanisms of epilepsy and the relationship between PCP and BBS.
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Meneghini, Marc D. „A MAP kinase-related pathway functions with the Wnt pathway to regulate anterior-posterior polarity in C. elegans /“. view abstract or download file of text, 2000. http://wwwlib.umi.com/cr/uoregon/fullcit?p9977911.
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Thesis (Ph. D.)--University of Oregon, 2000.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 76-79). Also available for download via the World Wide Web; free to University of Oregon users.
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Rocque, Brittany. „Role of planar cell polarity gene vangl2 in kidney development and disease“. Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123086.
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The Planar Cell Polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Vangl2 protein is central in the PCP pathway: its loss is embryonic lethal causing neural tube defects in mice and humans. In the kidney, PCP signaling is thought to be important for the organization of glomerular epithelial cells, podocytes, along the glomerular basement membrane. Podocyte cell protrusions, foot processes (FPs), are critical for kidney filtration functions; loss of FP architecture results in proteinuria and, in severe cases, focal segmental glomerulosclerosis (FSGS). Additionally, an effect of PCP pathway on podocyte shape, actin rearrangement and cell motility was previously described. We, therefore, hypothesized that the PCP pathway may be critical for glomerular development and function. We first characterized the Vangl2 expression pattern in developing mouse kidneys and showed that Vangl2 is dynamically expressed in developing glomeruli. To examine whether loss of Vangl2 affects podocyte differentiation and glomerular functions, we created a conditional podocyte-specific Vangl2 knockout mouse (V2-POD). V2-POD E17.5 embryos exhibit a delayed maturation of glomeruli compared with controls. In adult mice, we detected significantly smaller glomeruli, yet filtration functions remained unaffected. However, when challenged with a nephrotoxic agent, V2-POD mice displayed an exacerbated degree of both acute and long-term glomerular injury indicating a function of Vangl2 in both glomerular development and disease (described in Chapter 2).To ascertain the mechanism behind PCP signaling in podocytes, we used both in vivo and in vitro settings (described in Chapter 3). In a Looptail mouse with a ubiquitous germ-line mutation of Vangl2 gene, we detected a profound disruption of renal morphology and glomerular developmental delay. In cultured immortalized human podocytes, stimulation of the PCP pathway with the PCP ligand, Wnt5a, leads to nephrin internalization via clathrin-mediated endocytosis. Furthermore, nephrin does not appear to be targeted for degradation, but rather is held in endocytic vesicles upon stimulation of the PCP signaling. Based on our present and published observations, we propose that the PCP pathway functions to a) regulate proper actin rearrangement in podocyte FPs during glomerular development and maintenance and b) to mediate endocytosis of certain cell adhesion proteins that is important for proper podocyte differentiation. In summary, we uncovered that Vangl2 plays an important role in glomerular development and maintenance. Loss of Vangl2 leads to various defects in kidney morphogenesis and significantly impairs glomerular recovery after glomerular injury. Our work has implicated the PCP pathway as an important regulator of kidney development and function.La voie de signalisation de polarité des cellules planaires (PCP) est cruciale pour la morphogenèse des tissus. La protéine Vangl2 est un élément de premier plan de cette voie de signalisation : l'absence de Vangl2 résulte en des anomalies du tube neural chez l'Être Humain et la souris menant ainsi à la mort de l'organisme dès la phase embryonnaire. Au niveau du rein, on pense que la voie de signalisation PCP est importante pour l'organisation des podocytes (les cellules épithéliales glomérulaires) le long de la membrane basale glomérulaire. Les pédicelles de podocytes (des saillies de cellules épithéliales glomérulaires) sont indispensables afin que le rein assume ses fonctions de filtration : un défaut au niveau des pédicelles de podocytes aboutit à la protéinurie et même, dans des cas plus graves, à la glomérulosclérose segmentaire focale. On a précédemment rapporté que la voie de signalisation de PCP a une influence sur la morphologie des podocytes, sur leur motilité et sur le réarrangement de l'actine. On peut donc émettre l'hypothèse suivante : La voie de signalisation de PCP est critique au développement et au fonctionnement glomérulaire. Nous avons d'abord caractérisé le profil d'expression de Vangl2 dans des reins de souris en phase de développement puis nous avons démontré que l'expression de Vangl2 dans les glomérules est «dynamique». Pour déterminer si l'absence de vangl2 affecte la différenciation des podocytes et les fonctions glomérulaires, nous avons confectionné une souris Vangl2 knockout spécifique aux podocytes (V2-POD). À E17,5 embryonnaire, les glomérules de V2-POD connaissent un retard de maturation comparé aux souris contrôles. Chez les souris V2-POD adultes, bien qu'on y observe des glomérules d'une taille significativement plus petite que celles des souris contrôles, les fonctions de filtration glomérulaire ne sont pas affectées. Cependant, lorsque l'on induit des lésions glomérulaires chez ces mêmes souris, on remarque une exacerbation des dommages aux glomérules chez les souris V2-POD, que ces dommages soient aigües ou causées graduellement au cours du temps. Cela nous indique que Vangl2 joue un rôle dans le développement normal des glomérules (décrit au chapitre 2). Pour établir le mécanisme derrière la voie de signalisation de PCP chez les podocytes, l'étude a été faite in vivo et in vitro (comme décrit au chapitre 3). Chez la souris à queue en boucle (Looptail mouse) caractérisée par une mutation germinale ubiquitaire de Vangl2, on a noté une importante perturbation de la morphologie des reins et un décalage du développement glomérulaire (plus lent). Dans des podocytes humains immortalisés mis en culture, la stimulation de la voie de signalisation de PCP avec le ligand de PCP Wnt5a mène à une internalisation de néphrine par endocytose induite par la clathrine. Outre, il semblerait que la néphrine soit restée prisonnière d'une vésicule d'endocytose plutôt que d'être dégradée suite à la stimulation de signalisation PCP. En se fondant sur les observations nouvelles et celles de nos publications précédentes, on suggère que la voie de signalisation de PCP a pour fonction: a) de réguler le réarrangement d'actine dans les pédicelles de podocytes pendant le développement et l'entretien glomérulaire; b) d'induire l'endocytose de certaines protéines d'adhésion importantes pour la différentiation normale des podocytes. En conclusion, Vangl2 joue un rôle important dans le développement et l'entretien glomérulaire. La perte de Vangl2 se traduit par de nombreux défauts dans la morphogenèse rénale et par une détérioration significative de l'aptitude de régénérescence des glomérules suite aux lésions qui leur sont causées. Notre travail sous-tend que la voie de signalisation PCP est un régulateur des développements et fonctionnement rénaux.
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Pryor, S. E. „Planar cell polarity signalling and development of the early mammalian nervous system“. Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1401159/.
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The vertebrate planar cell polarity (PCP) pathway is an evolutionarily conserved signalling cascade which regulates numerous developmental processes. This thesis investigates the role of PCP signalling in two events, mammalian spinal neurulation and neural crest (NC) cell migration. In mouse embryos PCP signalling is required for initiation of neural tube closure, via regulation of midline convergent extension (CE). In this thesis, a genetic modifying role for the loop-tail (Vangl2Lp) mutation is shown to also predispose to failure of low spinal neurulation. Mutations in the core PCP gene Vangl2 increase the frequency and severity of spina bifida in the grainyhead-like-3 hypomorph curly tail (Grhl3ct/ct), a model of partially-penetrant NTDs. Affected Vangl2Lp/+;Grhl3ct/ct embryos exhibit abnormalities of axis elongation, suggesting a role for CE in spinal neurulation. Investigations of the mechanism underlying the Lp/ct interaction reveal two distinct types of effect: 1) Effects of expression of Vangl2Lp and Grhl3ct in different tissues: Vangl2 regulates midline CE and Grhl3 regulates proliferation of tail bud progenitors. These mutant effects likely summate, leading to severe spina bifida; 2) Cell-autonomous effects of Vangl2Lp and Grhl3ct co-expression in the same tissue: conditional genetic experiments suggest a requirement for Vangl2 and Grhl3 within the same cells during neurulation and evidence for a molecular interaction at the level of Rho-GTPase signalling is presented. In amphibia and fish, early NC migration is PCP-dependent, but this has not yet been studied in mammals. Vangl2Lp/Lp embryos display normal NC cell migration, despite many severe PCP-related defects, and migration of Vangl2Lp/Lp NC in vitro is comparable to Vangl2+/+. The closely related gene Vangl1 does not appear to compensate for loss of Vangl2. Acute down-regulation of Vangl2 specifically in the NC lineage does not cause migratory defects. Hence, the core PCP pathway is not required for early NC migration in the mouse.
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Pietra, Stefano. „Characterization of New Players in Planar Polarity Establishment in Arabidopsis“. Doctoral thesis, Umeå universitet, Institutionen för fysiologisk botanik, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-87838.
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Coordinated polarity and differentiation of cells in the plane of a tissue layer are essential to the development of multicellular organisms. Arabidopsis thaliana root hairs and trichomes provide model systems to study the pathways that control planar polarity and cell fate specification in plants. A concentration gradient of the plant hormone auxin provides an instructive cue that coordinates polar assembly of signalling complexes at plasma membranes of root epidermal cells; however, knowledge about additional players and cytoskeletal effectors driving cell polarization prior to hair emergence remains limited. On the other hand, epidermal cell fate specification is controlled by a well-characterized gene network of transcription factors that translate positional signals and cell-to-cell communication into tissue-wide patterning. Yet, new components are continuously found to interact with the patterning pathway, shedding light on its connections with diverse developmental processes. This thesis presents the SABRE (SAB) gene as a novel player in planar polarity establishment and root epidermal patterning. SAB is a large protein with sequence similarity to proteins present in all eukaryotes and affects planar polarity as well as orientation of cell divisions and cortical microtubules. Genetic interaction with the microtubule-associated protein gene CLASP further supports involvement of SAB in microtubule arrangement, suggesting a role for this gene in cytoskeletal organisation. Strikingly, SAB also interacts genetically with ACTIN7 (ACT7), and both ACT7 and its modulator ACTIN INTERACTING PROTEIN 1-2 (AIP1-2) contribute to planar polarity of root hair positioning. Cell-file specific expression of AIP1-2 depends on the epidermal-patterning regulator WEREWOLF (WER), revealing a connection between actin organization, planar polarity and cell fate specification. Consistent with this finding, SAB also functions in patterning of the root epidermis by stabilizing cell fate acquisition upstream of the core patterning pathway. These results unveil new roles for SAB in planar polarity and epidermal patterning and suggest that organization of the microtubule and the actin cytoskeleton are important to both planar polarity establishment and cell fate specification.Samordning av polaritet och differentiering av celler inom ett vävnadslager är avgörande för utvecklingen av multicellulära organismer. Rothår och bladhår hos Arabidopsis thaliana utgör modellsystem för att studera signalvägar som kontrollerar planpolaritet och specifikation av cellers öde hos växter. En koncentrationsgradient av växthormonet auxin ger en instruktiv signal som koordinerar polär hopsättning av signalkomplex vid plasmamembranet i rotepidermisceller; dock är kunskapen om ytterligare aktörer och hur cytoskelettets aktörer påverkar cellpolaritet innan rothår bildas begränsad. Vad gäller differentieringen av epidermala cellers öde kontrolleras dessa genom ett väl karakteriserat nätverk av transkriptionsfaktorer som överför positionssignaler och cell-till-cell kommunikation till vävnadsomfattande mönsterbildning. Fortfarande hittas dock nya komponenter som interagerar med signalvägarna för mönsterbildning, vilket ger nya insikter om dess förbindelser med diverse utvecklingsprocesser. Denna avhandling presenterar genen SABRE (SAB) som en ny aktör i etableringen av planpolaritet och mönsterbildning av rotepidermis. SAB är ett stort protein som har sekvenslikhet med proteiner som finns i alla eukaryoter och det påverkar planpolaritet, orientering av celldelning och kortikala mikrotubler. Genetisk interaktion med genen för det mikrotubuli-associerade proteinet CLASP stärker ytterligare inblandningen av SAB i organiserandet av mikrotubler och antyder att denna gen har en roll i organiserandet av cytoskelettet. Slående är att SAB även interagerar genetiskt med ACTIN7 (ACT7) och att både ACT7 och dess modulator ACTIN-INTERACTING PROTEIN1-2 (AIP1-2) bidrar till planpolaritet vid positionering av rothår. Cellfils-specifikt uttryck av AIP1-2 beror på den epidermala mönsterbildande genen WEREWOLF (WER), vilket påvisar ett samband mellan organisationen av aktin, planpolaritet och specifikationen av cellers öde. SAB fungerar även i mönsterbildning av rotens epidermis och stabiliserar förvärvet av cellöde uppströms av den centrala signalvägen för mönsterbildning. Dessa resultat visar på nya roller för SAB i planpolaritet och mönsterbildning av epidermis och indikerar att organiseringen av mikrotubler och aktin-cytoskelettet är viktiga både för etablerandet av planpolaritet och för specificeringen av cellers öde.
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Panzica, Domenico Alessio. „The roles of planar cell polarity signalling in maintaining the adult corneal epithelium“. Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=227224.
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Cells of the stratified adult corneal epithelium undergo centripetal migration throughout adult life from the edge of the cornea to the centre. To date nothing is known about the mechanism underpinning the oriented cellular migration. Failure to replenish apoptotic cells lost by desquamation from the superficial layer of the corneal epithelium leads to severe pathological conditions that may result in blindness. In this study we investigated the role of planar cell polarity (PCP) core proteins as the guidance cue for centripetal migration in the cornea. Cre-mediated conditional deletion of floxed alleles of the core PCP gene Vangl2 in the corneal epithelium and lens of adult mice was achieved. The effect of this deletion was studied by microscopic and immunohistological observation of the cornea compared to littermate controls, showing defects consistent with disrupted apical-basal polarity in mutant mice. Planar behaviour of the corneal epithelial cells was assayed by breeding the mutant alleles (Le-CreTg/-; Vangl2flox/flox) and the Looptail mouse (Vangl2Lp/+) onto an X-linked LacZ reporter transgene (XLacZ) background, demonstrating the importance of PCP core components for normal cell migration. In vitro directional migration studies were performed on Vangl2 and Frizzled6 knock-down human corneal epithelial cells following the application of direct current electric fields (DC-EFs), resulting in the reduction of directional migratory response to the DC-EF. This study showed for the first time roles for the planar cell polarity (PCP) signalling in orchestrating and coordinating cellular cues that drive oriented migration in the unwounded adult corneal epithelium. It is likely that mutations in PCP genes could lead to ocular surface abnormalities in humans.
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Genevet, A. „Control of cell polarity and growth by the Hippo pathway in Drosophila“. Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20453/.
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The Hippo (Hpo) signalling pathway comprises the kinases Hpo and Warts (Wts), the adaptors Salvador and Mats, the cytoskeletal proteins Expanded (Ex) and Merlin (Mer), the atypical cadherin Fat and the transcriptional co-factor Yorkie (Yki). This pathway has been shown to restrict tissue size through the control of cell division and apoptosis during development in Drosophila. In addition to their well-characterised overproliferation phenotype, adult epithelial cells mutant for the kinases Hpo and Wts present a hypertrophy of the apical domain. I examined the molecular basis of this apical hypertrophy and its impact on cell proliferation. In the wing imaginal disc epithelium, I observe increased staining for members of the apical polarity complexes aPKC and Crumbs as well as adherens junction components when Hpo activity is compromised, while baso-lateral markers are not affected. This increase in apical proteins is correlated with a hypertrophy of the apical domain and adherens junctions. Interestingly however, while the polarity determinant Crumbs is required for the accumulation of apical proteins, this does not appear to significantly contribute to the overproliferation defect elicited by loss of Hpo signalling. Therefore, the Hpo pathway controls growth and apical domain size via distinct mechanisms. In collaboration with the Thompson lab (CRUK LRI) we identified the WWdomain- containing protein Kibra (Kib) as a new member of the Hpo pathway. Kib, which colocalises and physically interacts with Mer and Ex, also promotes the Mer/Ex association. Furthermore, the Kib/Mer interaction is conserved in human cells. Loss of kib induces a hpo-like phenotype and genetic experiments place it upstream of the core kinase cassette. Finally, Kib binds to Wts and kib depletion in tissue culture cells induces a marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction. My work therefore suggests that Kib is part of an apical scaffold that promotes Hpo pathway activity.
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Visanuvimol, Jiravat. „The Role of vang-1/Van Gogh in Neuronal Polarity in Caenorhabditis elegans“. Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22762.
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During neuronal development, the axonal and dendritic projections are polarized and oriented along specific body axis. To further explore the molecular basis of neuritogenesis in vivo, we used the nematode Caenorhabditis elegans as a developmental model and performed a forward genetic screen to identify genes that specify the polarity of neurite outgrowth. We examined the VC4 and VC5 neurons, members of the six VC motor neurons using the Pcat-1::gfp transgene cyIs4. The VC motor neurons are ventrally located neurons that extend two processes. VC1, VC2, VC3, and VC6 extend axons along the anterior-posterior (A/P) axis; VC4 and VC5 extend axons around the vulva along a mediolateral left-right (L/R) axis perpendicular to the A/P axis. We identified and showed that vang-1/Van Gogh, a core component of planar cell polarity (PCP) signalling pathway, acts cell-autonomously in VC4 and VC5 neurons and non-autonomously from the epithelial cells to restrict neurite formation along the A/P axis. vang-1 mutant animals display ectopic neurites along the A/P axis. Using a candidate gene approach, we further identified and revealed two additional core members of PCP signalling, Prickle (PRKL-1) and Dishevelled (DSH-1), to play a role in A/P-directed neurite suppression. We also showed prkl-1 and dsh-1 genetically interact with vang-1 and VANG-1 is required to suppress A/P-directed neurite outgrowth from larval stage 4 to adulthood. Overexpression of VANG-1 results in a loss-of-function (lof) phenotype, suggesting that an appropriate level of VANG-1 activity is important. Additionally, vang-1/prkl-1, and dsh-1 may interact in parallel pathways. Our findings implicate PCP genes to play a previously unidentified role in maintaining polarized neuronal morphology by inhibiting neuronal outgrowth responses to environmental cues.
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Sánchez-Alvarez, Leticia. „Planar Cell Polarity Genes prkl-1 and dsh-1 Polarize C. Elegans Motorneurons during Organogenesis“. Thesis, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23513.
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The correct polarity of a neuron underlies its ability to integrate precise circuitries in
the nervous system. The goal of my thesis was to investigate the pathways that establish and
maintain neuron polarity/orientation in vivo. To accomplish this, I used bipolar VC4/5 motor
neurons, which innervate the C. elegans egg-laying musculature, as a model system. Vulval
proximal VC4/5 neurons extend axons in the left-right (LR) orientation, around the vulva;
whereas vulval distal VC1-3,6 neurons extend axons along the anterior-posterior (AP) axis.
A previous study showed that vang-1, a core planar cell polarity (PCP) gene, suppresses AP
axon growth in VC4/5 neurons. In order to identify new components of this pathway we
performed genetic screens for mutants with abnormal VC4/5 polarity/morphology. We
isolated and mapped alleles of farnesyl transferase b (fntb-1) and of core PCP genes, prickle-
1 (prkl-1) and dishevelled-1 (dsh-1); all of which display tripolar VC4/5 neurons, similar to
vang-1 lof. In prkl-1 and dsh-1 mutants, primary LR and ectopic AP VC4/5 axons are born
simultaneously, suggesting an early role in establishing polarity. In addition, prkl-1 and dsh-1
act persistently to maintain neuron morphology/orientation. Genetic analysis of double
mutants suggests that prkl-1 interacts with vang-1 in a common PCP pathway to prevent AP
axon growth, while dsh-1 also acts in a parallel pathway. Furthermore, prkl-1 functions cell
autonomously in neurons, whereas dsh-1 acts both cell autonomously and cell nonautonomously
in epithelial cells. Notably, prkl-1 overexpression results in unipolar VC4/5
neurons, in a dose-dependent manner. In contrast, dsh-1 overexpression in VC4/5 neurons
results in a lof phenotype, similar to vang-1 lof and overexpression phenotype. Remarkably,
prkl-1 overexpression restores normal VC4/5 polarity in dsh-1 and vang-1 mutants, which is
suggestive of a downstream role for prkl-1. Both PRKL-1 and DSH-1 are expressed in
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uniformly distributed puncta at the plasma membrane of VC4/5, similar to VANG-1;
suggesting that their asymmetric distribution is not critical for neuron polarity. Furthermore,
we found that the vulva epithelium induces prkl-1 expression in VC4/5; indicating a
functional relationship between the egg-laying organ and neuron morphology. Moreover, a
structure-function analysis of PRKL-1 revealed that the conserved PET domain and the Cterminal
region are crucial to prevent AP axon growth, whereas the three LIM domains are
dispensable for this role. In addition, we showed that dsh-1 also regulates the morphology of
AP-oriented PDE neurons. dsh-1 promotes the formation of PDE posterior axons, contrary to
its function in VC5 neurons; which indicates a context-dependent role for dsh-1 in neuronal
polarity. Altogether, this thesis implicates the PCP signalling pathway in a previously
unknown role, in establishing and maintaining neuronal polarity, by controlling AP axon
growth in response to organ-derived polarizing cues.
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Saavedra, Pedro Almeida Dias Guedes. „Pattern formation and planar cell polarity in Drosophila larval development : insights from the ventral epidermis“. Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708010.
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Zhao, Xuesong. „Role of the drosophila cadherin fat in regulating tissue size and planar cell polarity signaling /“. May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Staple, Douglas. „Understanding Mechanics and Polarity in Two-Dimensional Tissues“. Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-85622.
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During development, cells consume energy, divide, rearrange, and die. Bulk properties such as viscosity and elasticity emerge from cell-scale mechanics and dynamics. Order appears, for example in patterns of hair outgrowth, or in the predominately hexagonal pattern of cell boundaries in the wing of a fruit fly. In the past fifty years, much progress has been made in understanding tissues as living materials. However, the physical mechanisms underlying tissue-scale behaviour are not completely understood. Here we apply theories from statistical physics and fluid dynamics to understand mechanics and order in two-dimensional tissues. We restrict our attention to the mechanics and dynamics of cell boundaries and vertices, and to planar polarity, a type of long-ranged order visible in anisotropic patterns of proteins and hair outgrowth.
Our principle tool for understanding mechanics and dynamics is a vertex model where cell shapes are represented using polygons. We analytically derive the ground-state diagram of this vertex model, finding it to be dominated by the geometric requirement that cells be polygons, and the topological requirement that those polygons tile the plane. We present a simplified algorithm for cell division and growth, and furthermore derive a dynamic equation for the vertex model, which we use to demonstrate the emergence of quasistatic behaviour in the limit of slow growth. All our results relating to the vertex model are consistent with and build off past calculations and experiments.
To investigate the emergence of planar polarity, we develop quantification methods for cell flow and planar polarity based on confocal microscope images of developing fly wings. We analyze cell flow using a velocity gradient tensor, which is uniquely decomposed into terms corresponding to local compression, shear, and rotations. We argue that a pattern in an inhomogeneously flowing tissue will necessarily be reorganized, motivating a hydrodynamic theory of polarity reorientation. Using such a coarse-grained theory of polarity reorientation, we show that the quantified patterns of shear and rotation in the wing are consistent with the observed polarity reorganization, and conclude that cell flow reorients planar polarity in the wing of the fruit fly. Finally, we present a cell-scale model of planar polarity based on the vertex model, unifying the themes of this thesis.
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Crompton, Lucy Annabel. „Investigation into the role of planar cell polarity in axis formation of the early mammalian embryo“. Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485550.
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In the early mammalian embryo cells undergo differentiation into specific lineages, which are assembled into a blueprint for the matwe body plan. This blueprint consists of is the three definitive embryonic axis, anteriorposterior, dorso-ventral and left-right. The first axis to be established is the anterior-posterior axis. Two critical events in anterior-posterior axis development are the induction and migration of the Anterior Visceral Endoderm (AVE) at 5.5 days post coitum (dpc) and gastrulation at 6.5 dpc. The AVE is a signaling centre.required for anterior specification. Gastrulation is the process that generates the three germ layers. Both AVE migration and gastrulation involve epithelial cells undergoing rearr.engement and directed cell movements, however the underlying molecular mechanisms that control these cell movements remain unknown. This thesis explores a possible role for the Planar Cell Polarity (PCP) pathway during anterior-posterior axis development. The PCP pathway is an evolutionarily conserved pathway, which in Drosophila regulates tissue polarity and cell movements primarily through modification of the cytoskeleton. A core group of PCP proteins have been defined including the membrane recep.tor Frizzled, the cytoplasmic proteins Dishevelled and Prickle, and the transmembrane proteins Flamingo and Strabismus. They co-localize to form asymmetric complexes within the cell, which modulate cytoskeletal components thus resulting in changes in cell shape or position, or arrangement of a whole tissue. This work focuses on the Prickle orthologues Prickle 1, Prickle2 and Testin, and the Flamingo orthologues Ge/sr1-3. In the first place the expression patterns of these Prickle and Ge/sr family members were characterised between 5.5 and 8.0 dpc. Given their expression in the AVE and gastrulating cells Testin and Ge/sr1 were chosen for functional analysis. To study the role of Testin during embryonic development two approaches have been taken. A genetrap mutation that generates a null Testin allele was analyzed. In addition genetic interaction experiments with another PCP orthologue, Vangl1, were carried out. To examine the role of Celsr1 in A-P axis formation an inqucible dominant negative Celsr1 mutation was generated. This thesis reports the analysis of these PCP pathway mutations.
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Seo, Jung Hwa. „Mutations in the Planar Cell Polarity gene, Fuzzy, are associated with neural tube defects in humans“. Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106542.
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The planar cell polarity (PCP) pathway is evolutionally conserved from flies to vertebrate; it controls multiple cellular processes during embryonic development. One of such processes is neurulation, which gives rise to the brain and spinal cord. Mutations in the PCP genes in mice cause a very severe neural tube defect (NTD), called craniorachischisis, establishing that the PCP pathway is an important regulator of neural tube closure. NTDs are the second most common congenital malformation in humans. Since the etiology of NTDs in humans is complex and involves both genetic and environmental factors, the identifying of the causative genes/factors has been very difficult. Recently, however, mutations in the PCP genes, Vangl1 and Vangl2, were reported to contribute to the pathogenesis of a subset (~2%) of human NTDs, suggesting that other genes in the same pathway may account for some cases of NTDs in humans. Knockdown studies of another PCP gene, Fuzzy, in model animals revealed a wide spectrum of phenotypes including NTDs, defective convergent extension, abnormal Sonic hedgehog (Shh) signalling, and defects in ciliogenesis. In this project, we studied the role of Fuzzy in neural tube development in mammals as well as Fuzzy-dependent molecular mechanisms that contribute to the generation of primary cilium. We screened a human NTD cohort from Italy for mutations in Fuzzy and identified five non-synonymous disease-associated amino-acid variants. We have designed novel methods to ascertain an impact of mutations on ciliogenesis. We report here that Fuzzy mutations affect formation of primary cilium and ciliary length and impact directional cell movements. We therefore propose that mutations in Fuzzy may account for the subset of NTDs in humans. We established that Fuzzy delivers Rab8, an essential regulator of ciliogenesis, to the cilium and propose that loss of cilia seen in Fuzzy mutant is, at least partly, due to the loss of Rab8 at the cilium. In addition, we uncovered novel molecular mechanisms whereby Fuzzy affects canonical Wnt signalling. We report here that Fuzzy interacts with DVL2, a PCP protein. Fuzzy both recruits and delivers DVL2 to the primary cilium, consequently limiting the canonical PCP pathway.La voie de la polarité cellulaire planaire (PCP), conservée de la mouche aux vertébrés, contrôle plusieurs processus cellulaires au cours du développement embryonnaire telle que la neurulation qui permet le développement du cerveau et de la moelle épinière. Des mutations des gènes de la PCP chez la souris causent une forme très sévère des anomalies du tube neuronal (ATN), le craniorachischisis, suggérant ainsi que la PCP est un régulateur important de la fermeture du tube neuronal. Les ATN sont la deuxième malformation congénitale la plus courante chez les humains. Vu que l'étiologie des ATN chez les humains est complexe et implique à la fois des facteurs génétiques et environnementaux, l'identification des gènes/facteurs responsables s'avère difficile. Toutefois, les études récentes ont mis en évidence que les mutations des gènes de la PCP, Vangl1 et Vangl2, chez les humains contribuent à la pathogenèse de certains cas d'ATN (~2%), ce qui suggère que d'autres gènes de la même voie peuvent aussi être tenus responsable de certains cas d'ATN chez les humains. Les études de knock-out, dans les modèles animaux, d'un autre gène de la PCP, Fuzzy, ont révélé un large éventail de phénotypes dont les ATN, l'extension convergente aberrante, la signalisation Sonic hedgehog (Shh) anormale et les défauts dans la ciliogenèse. Dans ce projet, nous avons étudié le rôle de Fuzzy dans le développement du tube neuronal chez les mammifères ainsi que des mécanismes moléculaires Fuzzy-dépendant impliqués dans la formation du cil primaire. Nous avons examiné des mutations dans le gène Fuzzy dans une cohorte humaine d'ATN provenant d'Italie et identifié cinq substitutions non synonymes d'acides aminés associées à des maladies. Nous avons conçu de nouvelles méthodes pour déterminer l'impact des mutations sur la ciliogenène. Nous reportons, dans cette étude, qu'au moins une mutation dans le gène Fuzzy affecte la formation du cil primaire ainsi que sa longueur et les mouvements directionnels des cellules. Par conséquent, nous proposons que les mutations du gène Fuzzy peuvent être tenus responsable de certains cas d'ATN chez les humains.Dans ce travail, nous avons établi que Fuzzy recrute et/ou séquestre Rab8, un régulateur essentiel de la ciliogenène, et nous suggérons que la perte des cils observée chez les mutants de Fuzzy est en partie causée par l'absence du Rab8 au niveau du cil. De plus, nous avons découvert un nouveau mécanisme moléculaire via lequel Fuzzy affecte la signalisation de Wnt. Cette étude montre que Fuzzy interagit avec DVL2, une protéine de la PCP. Ainsi, Fuzzy recrute et délivre DVL2 au niveau du cil primaire limitant ainsi la voie canonique de la PCP.
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Yamana, Norikazu. „Rho/mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cell through mobilizing APC and c-Src“. Kyoto University, 2007. http://hdl.handle.net/2433/135658.
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Chen, Wei-Shen. „Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular planar cell polarity signaling in drosophila melanogaster /“. May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Gao, Qian. „A systems biology approach to multi-scale modelling and analysis of planar cell polarity in Drosophila melanogaster wing“. Thesis, Brunel University, 2013. http://bura.brunel.ac.uk/handle/2438/7478.
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Systems biology aims to describe and understand biology at a global scale where biological systems function as a result of complex mechanisms that happen at several scales. Modelling and simulation are computational tools that are invaluable for description, understanding and prediction these mechanisms in a quantitative and integrative way. Thus multi-scale methods that couple the design, simulation and analysis of models spanning several spatial and temporal scales is becoming a new emerging focus of systems biology. This thesis uses an exemplar – Planar cell polarity (PCP) signalling – to illustrate a generic approach to model biological systems at different spatial scales, using the new concept of Hierarchically Coloured Petri Nets (HCPN). PCP signalling refers to the coordinated polarisation of cells within the plane of various epithelial tissues to generate sub-cellular asymmetry along an axis orthogonal to their apical-basal axes. This polarisation is required for many developmental events in both vertebrates and non-vertebrates. Defects in PCP in vertebrates are responsible for developmental abnormalities in multiple tissues including the neural tube, the kidney and the inner ear. In Drosophila wing, PCP is seen in the parallel orientation of hairs that protrude from each of the approximately 30,000 epithelial cells to robustly point toward the wing tip. This work applies HCPN to model a tissue comprising multiple cells hexagonally packed in a honeycomb formation in order to describe the phenomenon of Planar Cell Polarity (PCP) in Drosophila wing. HCPN facilitate the construction of mathematically tractable, compact and parameterised large-scale models. Different levels of abstraction that can be used in order to simplify such a complex system are first illustrated. The PCP system is first represented at an abstract level without modelling details of the cell. Each cell is then sub-divided into seven virtual compartments with adjacent cells being coupled via the formation of intercellular complexes. A more detailed model is later developed, describing the intra- and inter-cellular signalling mechanisms involved in PCP signalling. The initial model is for a wild-type organism, and then a family of related models, permitting different hypotheses to be explored regarding the mechanisms underlying PCP, are constructed. Among them, the largest model consists of 800 cells which when unfolded yields 164,000 places (each of which is described by an ordinary differential equation). This thesis illustrates the power and validity of the approach by showing how the models can be easily adapted to describe well-documented genetic mutations in the Drosophila wing using the proposed approach including clustering and model checking over time series of primary and secondary data, which can be employed to analyse and check such multi-scale models similar to the case of PCP. The HCPN models support the interpretation of biological observations reported in literature and are able to make sensible predictions. As HCPN model multi-scale systems in a compact, parameterised and scalable way, this modelling approach can be applied to other large-scale or multi-scale systems.
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Carr, David A. „The Role of Farnesyltransferase β-subunit in Neuronal Polarity in Caenorhabditis Elegans“. Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23784.
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Little is known about the molecular components and interactions of the planar cell polarity pathway that regulate neuronal polarity. This study uses a prkl-1 induced backwards locomotion defect as an array to perform a prkl-1 suppressor screen in C. elegans looking for new components of the planar cell polarity pathway involved in the neuronal polarization of VC4 and VC5. The screen discovered twelve new alleles of vang-1, one new allele of fntb-1 and five new mutations in unknown polarity genes. fntb-1 encodes for the worm ortholog of Farnesyltransferase β-subunit and is important for neuronal polarization. Acting cell and non-cell autonomously, fntb-1 regulates the function and localization of prkl-1 through the recognition of a CAAX motif. Therefore, fntb-1 modifies prkl-1 to regulate the neuronal polarity of VC4 and VC5.
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Organisti, Cristina. „The planar cell polarity regulator Flamingo cooperates with Netrin/Frazzled signaling during axon targeting in the Drosophila embryonic CNS“. Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-181615.
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Han, Suhao. „Interaction of centrosomal component SPD-5 with Wnt signals in the control of cell polarity in Caenorhabditis elegans“. Diss., Kansas State University, 2012. http://hdl.handle.net/2097/14716.
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Doctor of PhilosophyDepartment of Biology
Michael A. Herman
All multicellular organisms consist of a variety of cell types. One of the mechanisms to generate this cellular diversity is the asymmetric cell division, which requires the establishment of cell polarity. In Caenorhabditis elegans hermaphrodites, 807 of 949 somatic cell divisions are asymmetric. The centrosome and the Wnt signaling pathway both have been shown to regulate cell polarity and subsequently asymmetric divisions in many model organisms. However, it is not clear whether the Wnt signaling pathway manipulates the cell polarity through specific cellular organelles, such as the centrosome. To address this question, we examined a centrosomal component, SPD-5, to see whether it cooperates with the Wnt signaling pathway to regulate certain asymmetric cell divisions. We showed that SPD-5, which was originally found to be critical for the embryonic development, also played a role during certain post-embryonic cell divisions in C. elegans. Specifically the asymmetric divisions of seam cells that required SPD-5 function were also known to be regulated by the Wnt signaling pathway. Thus the stem-cell like seam cell divisions could be an intriguing system to study the interaction of centrosomes and the Wnt pathway. We found that SPD-5 was required for a successful cell division, similar to other centrosomal components. This suggests that SPD-5 still functions as a centrosomal component during C. elegans post-embryonic development. It has been shown that establishment of seam cell polarity relies on the asymmetric localization of certain Wnt pathway components. Interestingly, we found that SPD-5 was required for the proper localization of several Wnt components in a way that was independent of a key MTOC (microtubule-organizing center) member γ-tubulin. In addition, SPD-5 genetically interacted with the Wnt pathway components APR-1/APC and POP-1/Tcf to regulate asymmetric divisions of seam cells. These data suggest that SPD-5 interacts with the Wnt signaling pathway in controlling the polarity of seam cells. Overall, our results suggest a novel role of SPD-5 in cooperating with the Wnt signaling pathway to regulate cell polarity and asymmetric cell division, in addition to its function as a centrosomal component.
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Davies, Alexander Lloyd. „Role of the frizzled signalling pathway in control of hair cell production and polarity in the developing inner ear“. Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399278.
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PALMERINI, VALENTINA. „STRUCTURAL AND FUNCTIONAL INSIGHTS ON THE DROSOPHILA TNFR GRINDELWALD, COUPLING LOSS OF CELL POLARITY AND NEOPLASTIC GROWTH“. Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/609735.
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Disruption of polarity and impairment of programmed cell death are signalling pathways of advanced epithelial tumors, whose progression often involves the activation of signalling controlled by TNF receptors, such as the JNK pathway. However, the link between loss of polarity and JNK pathway still remains elusive. In a disc-specific rn>avl RNAi screen aimed at finding new genes involved in neoplastic onset, a novel Drosophila TNFR was identified, named Grindelwald (Grnd). Grnd and the unique fly TNF Eiger activate the JNK pathway, and induce apoptosis or malignancy in a cell context-dependent manner. My PhD project focused on the characterization of the molecular mechanisms underlying Grnd activation and transduction of the JNK pathway.
Upon binding to Eiger, Grnd recruits to the intracellular membrane Traf2, the most upstream component of the JNK pathway, and activates the JNK cascade. To shed light on the mechanism of Grnd activation by Eiger, I determined the crystal structure of the extracellular domain (ECD) of Grnd, in isolation and in complex with Eiger. Grnd-ECD comprises a single cysteine-rich domain, organized in two modules, named X2 and C2, and stabilized by disulphide bridges. The crystal structure of the Eiger:Grnd complex showed that the Eiger-TNF domain folds in a typical “jelly-roll” antiparallel -sheet, and forms hetero-hexamers with three Grnd molecules. To map the interacting surface between Grnd and Eiger, we engineered point mutations and performed binding assays revealing that Thr51, His66-Asn67 of Grnd and Asp337, His388-Arg391, and Arg396-Arg401 of Eiger are essential for the nanomolar affinity between the ligand and the receptor. In vitro studies suggest that glycosylation on Asn332 of Eiger lowers the affinity between Eiger and Grnd. We are currently generating collaboratively Grnd mutant flies to assess the relevance of the Eiger-Grnd interaction in activating the JNK pathway and inducing the small-eye phenotype, or in promoting malignancy in scrib-/-;rasV12 clones.
Previous results showed that the JNK pathway was activated in polarity-deficient cells to drive neoplastic growth. In the rn>avl RNAi screen, Grnd, but not Eiger, was necessary for the JNK pathway to be induced. I showed that Grnd directly interacts with the polarity protein Veli, to promote hyper-proliferation and invasiveness. Collectively, these findings depict Grnd as the first TNFR able to couple cell polarity with tumor overgrowth.
One major goal of my project was also the identification of a Grnd orthologue in human, able to couple polarity and signal transduction. Biochemical analyses revealed that Fas is the only TNFR interacting with Veli and with the basolateral polarity protein Dlg1, and provided evidence that Dlg1 compete with Veli for binding to Fas. The relevance of these interactions for the Fas biology is currently under investigation.
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Gegg, Moritz Verfasser], Angelika [Akademischer Betreuer] [Schnieke und Heiko [Akademischer Betreuer] Lickert. „Identification and characterization of the novel planar cell polarity gene Flattop (Fltp) / Moritz Gegg. Gutachter: Heiko Lickert ; Angelika Schnieke. Betreuer: Angelika Schnieke“. München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1060825481/34.
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Zanconato, Francesca. „Dissecting TAZ biology: mechanisms and regulations“. Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3426291.
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The central theme of this thesis is TAZ, a transcriptional co-activator that works - together with its homologue YAP - as transducer of the mammalian Hippo pathway.
Since the beginning of my PhD training, I have been involved in the investigation of TAZ function and regulation in breast cancer stem cells. Our findings established TAZ as a molecular determinant of self-renewal and tumorigenic potential in breast cancer cells. Indeed, the vast majority of high grade breast tumors (known to be enriched with cancer stem cells) display a strong positive staining for TAZ, compared with normal mammary tissue and low grade tumors. Experiments described in the first part of this thesis show that TAZ protein is stabilized in cells that have undergone an epithelial-to-mesenchymal transition, or simply lost the apico-basal polarization proper to epithelial cells. Indeed, in polarized epithelial cells the basolateral determinant Scribble activates the Hippo kinases to inhibit TAZ; in depolarized cells (including cells in malignant carcinomas) this inhibitory mechanism is disabled and TAZ can accumulate. How TAZ overexpression modifies the cell to turn it into a cancer stem cell is the object of ongoing work. Part of these results was published in (Cordenonsi et al., 2011).
During the last year, I have collaborated on a second project, dealing with TAZ regulation by Wnt signaling (Azzolin et al., 2012). We have found that Wnt signaling activates TAZ along with β-catenin. This happens because, in the absence of Wnt signals, phosphorylated β-catenin drives TAZ degradation; Wnt stimulation thus leads to the parallel stabilization of β-catenin and TAZ. Experiments presented here show that β-catenin effectively inhibits TAZ activity in the absence of Wnt signaling, and that TAZ stabilization is instrumental in both physiological and pathological Wnt biological responses.Il tema centrale di questa tesi è TAZ, un co-attivatore trascrizionale che – insieme al suo omologo YAP – funge da trasduttore della Hippo pathway nei mammiferi. Dal primo anno di dottorato, ho partecipato allo studio della funzione e la regolazione di TAZ nelle cellule staminali del tumore al seno. I risultati ottenuti dimostrano che TAZ è un determinante molecolare della capacità di auto- rinnovamento (self-renewal) e delle proprietà tumorigeniche di cellule di tumore mammario. La maggioranza dei tumori di alto grado istologico (che contengono un numero elevato di cellule staminali tumorali) esprimono livelli di TAZ più alti rispetto al tessuto sano della ghiandola mammaria e ai tumori di basso grado istologico. Gli esperimenti descritti nella prima parte di questa tesi dimostrano che TAZ è stabilizzato – a livello di proteina – in cellule epiteliali che hanno subito una trasformazione mesenchimale, o hanno perso la polarità apico-basale tipica delle cellule epiteliali. Infatti, in cellule epiteliali polarizzate Scribble, un determinante basolaterale, attiva le chinasi della Hippo pathway ed inibisce TAZ; in cellule depolarizzate (come molte cellule nei carcinomi maligni) questo meccanismo è inattivo e TAZ si accumula. Come la stabilizzazione di TAZ modifichi le cellule per trasformarle in cellule staminali tumorali è oggetto di studi attualmente in corso. Parte di questi risultati è stata pubblicata in (Cordenonsi et al., 2011). Durante l’ultimo anno, ho collaborato ad un secondo progetto, dedicato alla regolazione di TAZ da parte di Wnt/β-catenina (Azzolin et al., 2012). I segnali Wnt attivano TAZ insieme a β-catenina. Ciò è dovuto al fatto che, in assenza di Wnt, β- catenina fosforilata porta TAZ al proteasoma; la stimolazione con Wnt determina quindi la stabilizzazione parallela di β-catenina e TAZ. Gli esperimenti qui presentati dimostrano che β-catenina inibisce l’attività biologica di TAZ in assenza di Wnt, e che la stabilizzazione di TAZ ha un ruolo funzionale nelle risposte biologiche (sia fisiologiche che patologiche) ai segnali Wnt.
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Organisti, Cristina [Verfasser], und Rüdiger [Akademischer Betreuer] Klein. „The planar cell polarity regulator Flamingo cooperates with Netrin/Frazzled signaling during axon targeting in the Drosophila embryonic CNS / Cristina Organisti. Betreuer: Rüdiger Klein“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1069743720/34.
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Schäfer, Simon Thomas [Verfasser]. „ATP6AP2 is critically involved in adult hippocampal neurogenesis and reveals stage-specific functions for Wnt/ß-Catenin and Wnt/Planar Cell Polarity (PCP) signaling / Simon Thomas Schäfer“. Greifswald : Universitätsbibliothek Greifswald, 2015. http://d-nb.info/1069389331/34.
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Donati, Antoine. „Planar polarization of a mono-ciliated epithelium : the zebrafish floor-plate“. Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS078.
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La polarité cellulaire planaire (PCP) des cils motiles permet de générer des flux directionnels dans les cavités corporelles des animaux. Cependant les mécanismes de cette polarisation sont mal compris. Nous utilisons ici le plancher de poisson-zèbre pour étudier ces mécanismes. A l'aide d'échantillons fixés et d'imagerie sur embryon vivant, nous montrons que le positionnement postérieur des cils du plancher est progressif et asynchrone entre cellules voisines. Au cours du développement, les corps basaux (CB, centrioles à la base des cils) passent de plus en plus de temps en contact avec la membrane postérieure et arrêtent de toucher la membrane antérieure. Nous étudions aussi le rôle de Par3 dans ce processus. Nous trouvons que Par3 est enrichi à la membrane postérieure avant le positionnement postérieur des cils. Aux stades précoces, Par3 forme des îlots aux jonctions apicales et les CB touchent les membranes antérieures et postérieures uniquement au niveau de ces îlots. De plus la surexpression de Par3 perturbe la polarisation. Ces résultats suggèrent un rôle clef de Par3 dans la polarisation du plancher. Nous trouvons enfin que la polarisation des îlots de Par3 est perturbée dans le mutant de PCP vangl2, ce qui pourrait expliquer les défauts de polarisation du plancher de ces mutantsPlanar cell polarization (PCP) of motile cilia allows directional fluid flow generation within body cavities. However the mechanisms underlying PCP of ciliated epithelia are still poorly understood. Here we use the zebrafish floor-plate (FP) to investigate these mechanisms. Using both fixed samples and live-imaging, we show that asymmetric cilia positioning at the posterior side of FP cells is a progressive and asynchronous process between neighbouring cells. As development proceeds, basal bodies (BB, modified centrioles at the base of cilia) spend more time in contact with the posterior membrane and stop making contacts with the anterior membranes. We investigate the role of Par3 in FP cells polarization. We find that Par3 is enriched at the posterior membrane, before the asymmetric positioning of cilia. Strikingly, at early stages, Par3 accumulates as patches at the level of apical junctions and BB only contact anterior or posterior membranes at the level of these patches. In addition, Par3 over-expression disrupts FP PCP. These results strongly suggest that Par3 is a critical player in FP polarization. Finally we show that in zebrafish vangl2 PCP mutants, Par3 patches intensity and polarisation are disrupted, which could explain FP polarization defects. Since Vangl2 is anteriorly enriched in FP cells, this suggests an antagonistic relationship between Par3 and Vangl2
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Allen, John C. „FGF4 Induced Wnt5a Gradient in the Limb Bud Mediates Mesenchymal Cell Directed Migration and Division“. BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4309.
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The AER has a vital role in directing embryonic limb development. Several models have been developed that attempt to explain how the AER directs limb development, but none of them are fully supported by existing data. I provide evidence that FGFs secreted from the AER induce a gradient of Wnt5a. I also demonstrate that limb mesenchyme grows toward increasing concentrations of Wnt5a. We hypothesize that the changing shape of the AER is critical for patterning the limb along the proximal to distal axis. To better understand the pathway through which Wnt5a elicits its effects, we have performed various genetic studies. We demonstrate that Wnt5a does not signal via the Wnt/β-catenin pathway. However, we show that Wnt5a mutants share many common defects with Vangl2 mutants suggesting that Wnt5a signals through the Wnt/planar cell polarity (PCP) pathway.