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1
Goupil, Alix. "Genome instability : from genome content variations to gene expression plasticity." Electronic Thesis or Diss., Université Paris sciences et lettres, 2021. http://www.theses.fr/2021UPSLS053.
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La plupart de nos cellules sont diploïdes possédant deux copies de chaque chromosome. Lors de la mitose, la formation d’un fuseau bipolaire avec un centrosome à chaque pôle permet la ségrégation correcte des chromosomes, essentiel au maintien de la stabilité génétique. Il existe néanmoins des variations du contenu chromosomique comme la polyploïdie, définit comme le doublement de l’ensemble des chromosomes et l’aneuploïdie, définie comme la perte ou le gain de chromosome entier. Bien qu’observées, la fréquence des cellules aneuploïdies dans les tissus d’un organisme sain reste controversée.De façon importante, la duplication du génome et l’aneuploïdie sont associées à des pathologies et sont considérées comme une caractéristique du cancer. En effet, un nombre anormal de chromosomes est souvent associé à une instabilité chromosomique. Toutefois le rôle et les implications de ces variations dans l’initiation et la progression de tumeur restent peu compris.J’ai d’abord étudié les conséquences de la polyploïdie sur la division des cellules. J’ai utilisé des approches in vivo et in vitro en induisant la polyploidisation par défaut de cytocinèse dans des cellules souches neurales de drosophile et des cellules cancéreuses humaines. L’analyse de leur mitose m’a permis de découvrir que la présence de chromosomes et de centrosomes en excès conduisait invariablement à la formation de fuseaux multipolaires. En modélisant les cellules polyploïdes, j’ai découvert qu’au-delà de la quantité, la conformation spatiale de l’ADN contribue à cette multipolarité. Des perturbations expérimentales au niveau de l’ADN et du fuseau m’ont permis de démontrer que la présence d’ADN en excès agit comme une barrière physique bloquant la coalescence des multiples pôles et par conséquent empêchant la bipolarité. De façon intéressante, j’ai réussi à restaurer la bipolarité en supprimant la « barrière d’ADN » par ablation avec laser ou en augmentant la longueur des microtubules pour contourner celle-ci. Alors que l’amplification centrosomale était considérée comme unique acteur, mes résultats identifient l’excès d’ADN comme contributeur clef de la multipolarité et de l’instabilité chromosomique typique des cellules polyploïdes.Puis, je me suis ensuite intéressée à l’aneuploïdie, dont la fréquence en contexte sain reste un sujet de débat intense. De plus, les outils développés jusqu’à présent pour évaluer le taux d’aneuploïdie manque d’une dimension temporelle. J’ai donc généré un outil génétique innovant de visualisation et de suivi des cellules aneuploïdes in vivo chez la drosophile. J’ai utilisé l’expression de la GFP comme gène rapporteur, contrôlée par le système GAL4/UAS et son inhibition par GAL80. Ainsi, la perte aléatoire du chromosome contenant la séquence du GAL80 entraine l’apparition d’un signal GFP dans les cellules aneuploïdes. Celles-ci peuvent donc être facilement détectées et suivies en temps-réel dans les tissus. Utilisant ce système, j’ai découvert que la perte de chromosome était un évènement très rare dans les tissus de la mouche. Cet outil combiné à d’autres marqueurs fluorescents et/ou utilisé dans divers contextes génétiques pourrait aider à la compréhension de la genèse et du devenir des cellules aneuploïdes in vivo.De plus, j’ai constaté que le cerveau de la larve présentait un nombre important de cellules GFP. De manière surprenante, ces cellules ne résultaient pas de la perte de chromosomes mais de la perte d’expression du gène GAL80. Ces résultats inattendus ont de fortes implications pour la communauté des drosophilistes car cela peut mener à des faux positifs dans les expériences de génération de clones. J’ai aussi découvert que les cellules souches neurales présentaient un mosaïsme dans l’expression des gènes, qui diffèrent d’autres organes et s’adaptent à des stimuli environnementaux. Ceci représente possiblement un niveau de plasticité dans le cerveau nécessaire à la diversité neuronale, l’adaptation et la survieMost animal cells are diploid, containing two copies of each chromosome. Establishment of proper bipolar mitotic spindle containing two centrosomes, one at each pole contributes to accurate chromosome segregation. This is essential for the maintenance of genome stability, tissue and organism homeostasis. However, numerical deviations to the diploid set are observed in healthy tissues. Polyploidy is the doubling of the whole chromosome set and aneuploidy concerns the gain or loss of whole chromosomes. Importantly, whole genome duplications and aneuploidy have also been associated to pathological conditions. For example, variations to genome content are associated with chromosome instability and cancer development, however their exact contribution to cancer genome remains poorly understood.In the first part of my PhD project, I investigated the consequences of polyploidy during cell division. I found that the presence of extra DNA and extra centrosomes generated invariably multipolar spindles. Then I identified contributors to the multipolar status using in vivo approaches in Drosophila neural stem cells and in vitro culture of cancer cells. Further I combined DNA and spindle perturbations with computer modelling and found that in polyploid cells, the presence of excessive DNA acts as a physical barrier blocking spindle pole coalescence and bipolarity. Indeed, laser ablation to disrupt and increase in microtubule stability and length to bypass the DNA-barrier could rescue bipolar spindle formation. This discovery challenges the current view that suggested extra-centrosomes as only contributor to spindle multipolarity and provides a rational to understand chromosome instability typical of polyploid cells.The aim of the second part of my PhD project was to generate a novel tool to quantitively probe chromosome loss in vivo in Drosophila tissues. Aneuploidy has been observed in various physiological tissues, however the frequency of this error remained highly debatable. In addition, tools developed so far to assess aneuploidy lack a temporal dimension. To circumvent this, I used the expression of a GFP report gene driven by the GAL4/UAS system and its inhibition by GAL80. In principle, the random loss of the chromosome carrying the GAL80 sequence leads to GFP appearance in aneuploid cells that can therefore be followed in live tissues. I found that chromosome loss was extremely infrequent in most tissues of the wild type fly. This tool combined with fluorescent marker and/or tested in various genetic background, might help understanding mechanisms behind aneuploidy genesis and outcome in vivo.While developing this tool, I discovered that in the larval brain, GFP cells where not a by-product of chromosome loss but rather an unexpected mis-regulation in the expression of the GAL80 gene. These results have strong implications for the Drosophila community as it can result in false positive in clonal experiments. Further, I discovered a mosaicism and plasticity of the Drosophila brain in neural stem cells for gene expression which differs from other organs and that is influenced by environmental stimuli. This possibly reflects a certain level of plasticity in the brain necessary for neuronal diversity, adaptation and survival
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Thomas, Alexandre. "Rôle des microtubules lors de la division asymétrique des neuroblastes chez Drosophila melanogaster." Thesis, Rennes 1, 2020. http://www.theses.fr/2020REN1B012.
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Le neuroblaste de D. melanogaster est une cellule souche neurale qui se divise de façon asymétrique pour former un nouveau neuroblaste, et une GMC engagée dans une voie de différenciation. Cette division est asymétrique par la ségrégation différentielle de déterminants d’identité cellulaire, hérités par les deux cellules filles, mais également asymétrique par la taille, où le neuroblaste est plus grand que la GMC. Initialement deux voies ont été identifiées, la polarité cellulaire et le fuseau central, pour le contrôle du positionnement asymétrique du sillon de division dans ces cellules. Nous avons révélé que la détermination et le maintien de la position du sillon de division requièrent un troisième mécanisme reposant sur les microtubules périphériques. Cette sous-population de microtubules est observée pendant la cytokinèse au contact du sillon de division. De plus, nous avons démontré que la position du fuseau central est spatialement séparée de la position du sillon de division, en étant légèrement décalée vers le pôle apical, suggérant qu’il n’est pas requis à sa détermination. Par ailleurs, nous avons mis en évidence que la diminution des microtubules périphériques est associée à une relocalisation du sillon de division à la position du fuseau central, et à pour conséquence finale de mener à une division moins asymétrique. En conclusion cette étude révèle qu’un troisième mécanisme, dépendant des microtubules périphériques, est essentiel à la fidélité de l’asymétrie de division des neuroblastes chez Drosophila melanogasterD. melanogaster neuroblast is a neural stem cell which divides asymmetrically to generate a self-renewing neuroblast, and a GMC committed in a differentiation pathway. This division is asymmetric by the differential segregation of cell fate determinants, inherited by the two daughter cells, but also asymmetric by the size, where the neuroblast is larger than the GMC. Originally two pathways have been identified, cell polarity and central spindle, for the control of asymmetric cleavage furrow positioning in these cells. We revealed that the determination and maintenance of cleavage furrow position require a third mechanism involving the peripheral microtubules. This microtubule sub-population is observed during cytokinesis in contact with the cleavage furrow. Moreover, we showed that the position of the central spindle is spatially separated from the cleavage furrow position, being slightly shifted toward the apical pole, suggesting that it is not required for its determination. Furthermore, we highlighted that the diminution of peripheral microtubules is associated with a relocalisation of the cleavage furrow toward the central spindle position, leading to a less asymmetric division. To conclude this study reveals that a third mechanism, depending on peripheral microtubules, is essential for the fidelity of the neuroblast asymmetric division in Drosophila melanogaster
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Chaulet, Maxime. "Rôle du cil primaire dans la migration des neuroblastes du courant de migration rostrale." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS191.
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L'objectif de ma thèse a été de mieux comprendre les mécanismes sous tendant le rôle du cil primaire (CP) dans la migration neuronale. Notre modèle d’étude est la migration dans le courant de migration rostrale (CMR) chez la souris post-natale et adulte. Les neurones du CMR présentent une migration saltatoire alternant pause et nucléokinèse avec un mouvement stéréotypé du centrosome. Dans une première étude, aux résultats encore préliminaires, nous avons comparé la migration entre la souris post-natale (P10) et jeune adulte (P30) par imagerie sur tranche aigüe de cerveau, ainsi que l'effet d'une ablation génétique du CP à ces deux âges. Nous observons que les migrations diffèrent entre les deux âges et que l'ablation génétique du CP affecte différentiellement les paramètres de migration. Dans une deuxième étude, bientôt soumise pour publication, nous avons analysé la dynamique de l’AMPc au cours de la migration postnatale. Nous avons observé la présence cyclique d’un hotspot d’AMPc au centrosome, sous le CP. Nous montrons que l’AMPc produit dans le cil diffuse au centrosome et active localement la Protéine Kinase A dépendante de l’AMPc (PKA). L’ablation génétique du CP et le knock-down de l’adénylate cyclase 3 ciliaire mènent à une disparition du hotspot. Ils affectent également la migration avec un défaut de couplage centrosome/noyau conduisant à une altération de la nucléokinèse, ce qui est récapitulé par la délocalisation génétique de la PKA. Nous montrons donc que le centrosome et le CP agissent comme une unité de signalisation unique liée par la diffusion de l'AMPc ciliaire, ce qui régule la rythmicité de la migration saltatoire au centrosomeThe aim of my thesis was to better understand the mechanisms underlying the role of the primary cilium (PC) in neuronal migration. Our study model is the tangential migration in the rostral migratory stream (RMS) in the postnatal and adult mice. Neuroblasts of the CMR show a saltatory migration with pause and nucleokinesis and a stereotyped centrosome movement. In a first study with preliminary results, we compared the migration between postnatal (P10) and young adult (P30) stages by live imaging on acute brain slices, as well as the effect of genetic ablation of the PC at these two ages. We showed that migrations are different between these two stages and that genetic ablation of the PC impaired differentially migration parameters. In a second study, submitted for publication soon, we analysed cAMP dynamics during postnatal migration. We observed a dynamic cAMP hotspot cyclically at the centrosome, at the basis of the PC. We show that ciliary-produced cAMP diffuses to the centrosome, where it activates locally the cAMP-dependent Protein Kinase A (PKA). Genetic ablation of the cilium and knock-down of the ciliary Adenylate Cyclase 3 lead to the hotspot disappearance. They also affect migration with defective centrosome/nucleus coupling leading to altered nucleokinesis, which is recapitulated by PKA genetic delocalization. We thus show that PC and centrosome act as a signalling unit, linked by ciliary cAMP diffusion regulating the rhythmicity of salutatory migration at the centrosome
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Blanc, Étienne. "Identification de gènes associés à la dissémination métastatique dans un modèle de neuroblastes malins humains." Paris 11, 2004. http://www.theses.fr/2004PA11TO30.
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Boudannaoui, Saïda. "Expression des potentialites adrenergiques acquises lors de l'induction neurogene par des neuroblastes embryonnaires en differenciation in vitro." Toulouse 3, 1988. http://www.theses.fr/1988TOU30118.
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La neuroembryologie concerne les potentialites de differenciation neuronale acquises, lors de l'induction neurogene, par les cellules embryonnaires cibles. Etude de l'expression initiale du phenotype adrenergique, dans les neuroblastes embryonnaires d'amphibien en differenciation in vitro. Les systemes metaboliques responsables de la neurotransmission catecholaminergique se mettent en place et sont donc d'ores et deja acquis, des la fin de la gastrulation. La presence du chordomesoderme dans le microenvironnement de ces neuroblastes stimule leur differenciation. Colocolisation de deux enzymes marqueurs de la differenciation adrenergique au niveau des cellules chordales, elles memes capable de biosynthetiser la dopamine et la noradrenaline. Diverses sous-populations neuronales existent d'emblee tres precocement dans l'ensemble du neurectoderme
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Boudannaoui, Saïda. "Expression des potentialités adrénergiques acquises lors de l'induction neurogène par des neuroblastes embryonnaires en différenciation in vitro." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb376121292.
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Butruille, Lucile. "La neurogénèse hypothalamique adulte : sensibilité à la photopériode, devenir des neuroblastes et rôle dans la fonction de reproduction." Thesis, Tours, 2017. http://www.theses.fr/2017TOUR4032/document.
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De nombreuse études ont mis en évidence la présence de processus neurogéniques dans l'hypothalamus adulte, une structure du diencéphale impliquée dans la régulation de nombreuses fonctions physiologiques. L’objectif de ma thèse a consisté à étudier les mécanismes de plasticité, tels que la neurogenèse adulte, et leur implication dans le contrôle neuroendocrinien de la fonction de la reproduction. Chez le mouton, une espèce saisonnée, la reproduction est contrôlée par la photopériode. Les variations saisonnières de la durée du jour entrainent des variations saisonnières du taux de prolifération et du nombre de nouveaux neurones. Après avoir identifié les composants cellulaires de la niche neurogénique hypothalamique dans cette espèce, nous avons démontré leur sensibilité à la photopériode. Une analyse longitudinale en neuroimagerie nous permettra de déterminer le devenir des nouveaux neurones hypothalamiques. Une étude fonctionnelle réalisée chez la souris a démontré que les cellules hypothalamiques en division qui expriment la GFAP possèdent un potentiel neurogénique et que leur ablation conduit à la perte de la fonction de reproduction chez le mâleNumerous studies have demonstrated the presence of neurogenic processes in the adult hypothalamus, a diencephalon structure involved in the regulation of many physiological functions. The objective of my thesis was to study the mechanisms of plasticity, such as adult neurogenesis, and their involvement in the neuroendocrine control of the reproductive function. In sheep, a seasonal species, reproduction is controlled by the photoperiod. Seasonal variations in the duration of the day lead to seasonal variations in the proliferation rate and in the number of new neurons. After identifying the cellular components of the hypothalamic neurogenic niche in this species, we demonstrated their sensitivity to photoperiod. A longitudinal analysis in neuroimaging will aimed to determine the fate of new hypothalamic neurons. A functional study in mice showed that dividing hypothalamic GFAP positive cells have a neurogenic potential and their ablation leads to severe impairment of the reproductive function in the male
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MAS, CHRISTOPHE. "Clonage et caracterisation de genes impliques dans la proliferation des neuroblastes du telencephale un strategie d'identification de genes candidats a des maladies du neurodeveloppement." Paris 7, 1999. http://www.theses.fr/1999PA077156.
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Pour identifier des genes impliques dans les maladies complexes du neurodeveloppement, nous avons developpe une strategie qui associe une hypothese physiopathologique a une localisation candidate. En effet, des genes impliques dans la proliferation des neuroblastes du telencephale ont ete trouves mutes chez des enfants atteints de retard mental. On peut donc faire l'hypothese que des genes qui s'expriment lors de cette etape critique pourraient etre a l'origine d'autres maladies du neurodeveloppement telles que la microcephalie ou l'autisme. Afin d'isoler ce type de genes, nous avons par la technique du differential display (dd-rt pcr) compare les populations d'arn messagers du telencephale de la souris a 10. 5 jours embryonnaires a celles de regions plus posterieure du cerveau embryonnaire qui sont plus avancees dans leur differenciation. Par une approche de genomique comparative inter-especes, les orthologues humains des genes ainsi isoles ont ete identifies, puis positionnes sur le genome au moyen des informations issues de collections d'hybrides somatiques d'irradiation. Cette strategie nous a permis d'isoler 50 cdnas candidats dont 42% correspondent a des genes connus et 58% representent de nouveaux genes. Parmi ces genes, cinq sont positionnes sur des locus lies au retard mental et deux sur des locus de susceptibilite a l'autisme. Ainsi, nous avons clone un nouveau gene, rp42, localise au niveau du locus 6q16 du chromosome 6. Par cette approche, nous avons egalement clone le gene codant une immunophiline, fkbp25, dont nous avons pu montrer, sur un modele de culture in vitro de cellules souches de telencephale, que la localisation intra-cellulaire change avec la differenciation neuronale. Enfin, ce travail a permis de cloner un nouveau gene, nibrin. L'orthologue humain de ce gene est a l'origine du syndrome de nijmegen, une maladie autosomale recessive qui se caracterise par une immunodeficience et dont le phenotype neurologique est une microcephalie.
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L'Hostis-Guidet, Anne. "Des xénopes transgéniques pour l’étude de la neurogénèse : analyse et propriétés fonctionnelles de neuroblastes exprimant un gène rapporteur sous contrôle du promoteur de NeuroD." Rennes 1, 2007. http://www.theses.fr/2007REN1S139.
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L’activité électrique impliquée dans la neurogenèse au cours du développement embryonnaire chez les vertébrés est sous le contrôle de perméabilités calciques dont la caractérisation nécessite de pouvoir repérer les neuroblastes. Des lignées transgéniques exprimant la protéine EGFP sous contrôle de promoteurs de facteur de différenciation neuronale (NeuroD) ou de marqueur neuronal (Neuro β-tubuline) ont été produites chez l’amphibien Xenopus laevis. Chez ces animaux, l’expression du transgène est restreinte aux neurones et à des cellules indifférenciées du système nerveux. Des analyses par imagerie calcique en microscopie confocale suggèrent que les cellules exprimant l'EGFP sous contrôle du promoteur de NeuroD ont des propriétés fonctionnelles différentes des cellules ne l'exprimant pas. La combinaison de la transgenèse et de l'imagerie fonctionnelle permet d'envisager d’étudier et de caractériser les neuroblastes exprimant le facteur bHLH NeuroDElectrical activity involved in neurogenesis during embryonic development of vertebrates is dependant of calcium permeabilities whose characterization requires the ability to locate neuroblasts. Transgenic lines expressing EGFP under the control of the NeuroD (neuronal differentiation factor) and the Neuro β-tubulin (neuronal marker) promoters were produced in Xenopus laevis. The transgene expression is restricted to neurons and non differentiated cells exclusively in nervous system in these transgenic animals. Confocal calcium imaging suggests that EGFP expressing cells with the NeuroD promoter would have different functional properties compared to cells without transgene expression. The combination of transgenesis and functional cellular imaging is a promising tool for characterization of neuroblasts expressing bHLH NeuroD factor
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Basille, Magali. "Contribution à l'étude des récepteurs du pituitary adenylate cyclase-activating polypeptide (PACAP) au cours de l'ontogénèse du cervelet de rat. Recherche d'une activité trophique potentielle du PACAP sur les neuroblastes cérébelleux." Rouen, 1998. http://www.theses.fr/1998ROUES010.
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Le pituitary adenylate cyclase-activating polypeptide (PACAP) est présent en quantités non négligeables dans le cervelet de rat au cours des trois semaines qui suivent la naissance c'est à dire pendant la période de multiplication, migration et différenciation des cellules granulaires, suggérant un rôle neurotrophique du PACAP dans le cervelet des mammifères au cours du développement. L'ontogénèse des sites de liaison du PACAP par autoradiographie quantitative dans le cervelet immature du rat a démontré une expression transitoire des sites de liaison au niveau de la couche granulaire externe (CGE) et de la médulla, depuis la naissance jusqu'au 25ème jour de vie postnatale. La caractérisation pharmacologique des sites de liaison présents dans la CGE a révélé qu'il s'agit de récepteurs PVR1 de haute affinité pour le PACAP et de faible affinité pour le VIP. Sur des cultures de neuroblastes cérébelleux, le PACAP stimule de façon dose-dépendante la production d'AMPc et d'inositols phosphates. En revanche, le VIP est 100 fois moins efficace sur l'activité adenylyl cyclasique et sans effet sur le métabolisme des phosphoïnositides. L'activation des récepteurs PVR1 au niveau des cellules granulaires induit une stimulation de la phospholipase C via une protéine G sensible à la toxine pertussique, indépendemment de son effet stimulateur sur le système adénylyl cyclasique. La présence du PACAP et de ses récepteurs dans le cervelet immature et l'activation de plusieurs systèmes de transduction suggèrent que le PACAP pourrait être impliqué dans l'histogénèse du cortex cérébelleux. L'administration de PACAP pendant 24 ou 48 heures sur des neuroblastes cérébelleux en culture provoque une augmentation de la survie cellulaire alors que le VIP est 1000 fois moins actif. Cet effet du PACAP est spécifiquement bloqué par l'antagoniste PACAP(6-38). De plus, le PACAP induit une augmentation du nombre et de la longueur des neurites. Ces données démontrent que, in vitro, le PACAP exerce un effet neuroprotecteur sur les cellules granulaires immatures, suggérant un rôle physiologique du PACAP dans le développement du cervelet de rat.
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Lode, Holger Nikolaus. "Strategien zur Immuntherapie beim Neuroblastom." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970421214.
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Lode, Holger N. "Strategien zur Immuntherapie beim Neuroblastom." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/13902.
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Das Neuroblastom ist ein vom sympathischen Nervensystem ausgehender neuroektodermaler maligner Tumor des Kleinkindesalters. Bei über 50% der Neuroblastom-Ersterkrankungen liegt bereits das disseminierte Stadium 4 vor, das eine infauste Prognose hat. Eine wirksame Behandlung des Stadium 4 Neuroblastoms stellt deshalb nach wie vor eine der größten Herausforderungen der pädiatrischen Onkologie dar: Die Gesamtüberlebensrate von 20-25% der Kinder, die an dieser bösartigen Krankheit leiden, konnte während der letzten zwei Jahrzehnte trotz neuer Chemotherapie-Protokolle nicht wesentlich verbessert werden. Aus diesem Grund gibt es zunehmend Bestrebungen sich um Therapiealternativen zu bemühen. In dieser Arbeit werden die derzeit möglichen immunologischen Strategien zur Behandlung des Neuroblastoms abgehandelt.Neuroblastoma is a neuroectodermal malignancy of early childhood derived from sympathetic nervous tissue. At initial diagnosis over 50% of patients present with disseminated stage 4 disease which has a dismal prognosis. Effective treatment of patients with stage 4 neuroblastoma remains a major challenge in pediatric oncology. Despite novel therapeutic approaches including chemotherapy and autologous stem cell transplantation the overall survival rate of only 20-25% did not improve over the last two decades. Therefore, a lot of effort has been made to develop novel alternative therapies. This thesis summarizes possible immunotherapeutic strategies for the treatment of neuroblastoma.
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Wahle, Philipp. "Transcriptome dynamics in early Drosophila development at tissue and single-cell resolution." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/19976.
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Das Nervensystem von Drosophila melanogaster entwickelt sich aus dem Neuroectoderm entlang der anterior-posterioren Axe des Embryos. Dieses Gewebe unterteilt sich in drei Expressionsdomänen, die von ventral nach dorsal durch Expression der drei Homöobox-Transkriptionsfaktoren vnd, ind und msh charakterisiert sind. Vnd und Ind wurden als notwendig und ausreichend beschrieben, um die Zellidentitäten ihrer jeweiligen Gewebe zu determinieren. Um zu untersuchen, wie diese Transkriptionsfaktoren agieren, um ihre jeweiligen Zelltypen hervorzubringen, habe ich die genomweiten Genexpressionsmuster dieser verwandten Gewebe in Wildtyp-Embryos und in einer vnd-Mutante bestimmt. Ich fand heraus, dass anstelle eines Gewebes, das der IC-Domäne ähnelt, die Vnd-Mutante ein Gewebe hervorbringt, das neuronale Charakteristika zum grossen Teil verloren hat. Ich habe gefunden, dass der Transkiptionsfaktor "eyeless" bei ektopischer Expression in der VC den Vnd-Nervensystemphänotyp phänokopiert und ein ähnliches DNA-Bindemuster aufweist wie Vnd. Unsere Daten lassen vermuten, das Vnd sowohl als direkter Aktivator von VC-spezifischen Genen als auch als direkter Repressor von nicht-neuronalen Genen wirkt.
Um die zeitlich-örtliche Auflösung weiter zu erhöhen, habe ich mit Nikolaos Karaiskos kollaboriert, um Einzelzell-Transkriptome von Embryos einer einzigen embryonalen Stufe zu generieren und einen Genexpressions-Atlas des frühen Drosophila-Embryos mit Einzelzellauflösung zu erstellen der die nahezu genomweite Genexpression fast jeder Zelle zu rekapitulieren. Um die Nützlichkeit der Plattform zu demonstrieren, untersuchten wir Expressionsmuster von Genen, die an der Hippo-Signalkaskade beteiligt sind. Wir prognostizierten Hippo-Signalaktivität in bestimmten Bereichen des Embryos und zeigten, dass der Hippo-Signalweg die synchronisierte Zellteilung in diesen Bereichen unterbricht.The embryonic nervous system of Drosophila melanogaster derives from the neurogenic ectoderm, which is subdivided into three distinct domains. Several key transcription factors show expression exclusive to individual columns and endow their expression domains with characteristic identities. The genes vnd and ind, for example, are homeodomain transcription factors expressed in two columns. Both have been argued to be necessary and sufficient to confer the ventral column or intermediate column fates. To address the question how these transcription factors confer identities to their expression domains I determined the transcriptomic profile of these tissues in wild type and a Vnd mutant embryos. In order to do this, I established a protocol that allowed me to sequence the transcriptomes in developing embryos with spatio-temporal resolution. I found that upon knockout of Vnd, the ventral column largely looses its neurogenic identity rather than converting its fate, as models would predict. I identified Eyeless as a novel candidate transcription factor that shapes early nerve cord identities. Furthermore the data indicates that in Vnd acts as both, activator and repressor. Excessive co-binding with the GAGA-factor GAF suggests a mechanism by which this activation might be achieved. To push spatio-temporal resolution towards the single cell level, I collaborated with Nikolaos Karaiskos to extract single cell transcriptomes of a single developmental stage. This has allowed us to establish a digital single-cell resolved transcriptomic map of a single developmental stage. We used this map to predict expression patterns of thousands of genes with striking accuracy. We identified the Hippo signaling pathway as a spatially regulated pathway in early embryos and showed that it directs the interruption of cell cycle synchronicity in specific areas of the embryo.
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Harris, Stephen. "The characterisation of two enhancer trap lines expressed in the embryonic nervous system of Drosophila melanogaster." Thesis, University of Warwick, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282431.
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Skowron, Matthias Raphael. "Analyse stadiumspezifisch exprimierter Gene im Neuroblastom." Köln Deutsche Zentralbibliothek für Medizin, 2009. http://d-nb.info/99930478X/34.
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Niemann, Catherina-Annika [Verfasser]. "Querschnittsymptomatik bei Neuroblastom / Catherina-Annika Niemann." Köln : Deutsche Zentralbibliothek für Medizin, 2010. http://d-nb.info/1006160515/34.
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Connell, Marisa. "Myosin Dynamics in Drosophila Neuroblasts Lead to Asymmetric Cytokinesis." Thesis, University of Oregon, 2013. http://hdl.handle.net/1794/13000.
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Cells divide to create two daughter cells through cytokinesis. Daughter cells of different sizes are created by shifting the position of the cleavage furrow. The cleavage furrow forms at the position of the metaphase plate so in asymmetric cytokinesis the spindle is shifted towards one pole. Unlike most systems, Drosophila neuroblasts have a centrally localized metaphase plate but divide asymmetrically. Drosophila neuroblasts divide asymmetrically due to the presence of a polarized myosin domain at the basal pole during mitosis. I investigated the mechanism by which the basal myosin domain produces asymmetric cytokinesis and the pathway regulating this domain.
We tested several mechanisms by which the basal myosin domain could lead to asymmetric cytokinesis. Based on surface area and volume measurements, I demonstrated that asymmetric addition of new membrane is not involved. I determined that neuroblasts exhibit asymmetric cortical extension during anaphase with the apical pole extending 2-3 times more than the basal pole. Mutants that lose basal myosin extend equally at both poles supporting this model. Mutants that retain apical myosin exhibited symmetric cortical extension but still divided asymmetrically, demonstrating that asymmetric cortical extension is not required for asymmetric cytokinesis. Observations of the mitotic spindle show that the cleavage furrow forms at a position biased towards the basal pole when compared to the position of the metaphase plate even though this position is still equidistant between the centrosomes. I observed that midzone components shift basally in a basal domain dependent manner suggesting that contraction of the basal domain leads to new microtubule-cortex interactions at a position away from the spindle midzone.
I demonstrated that the basal domain is regulated by the heterotrimeric G protein, Gβ13F, which is activated by Pins. In Gβ mutants, the localization of all basal components (myosin, anillin, and pavarotti) is lost and the cells divide symmetrically. Although the basal domain is contiguous with equatorial myosin, it is not regulated by the same pathway and photobleaching experiments indicate that they exhibit different behaviors during anaphase suggesting a difference in temporal regulation.
This dissertation includes previously published coauthored material.
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Delgado-Garcia, Lina Maria [UNESP]. "Estudo da proliferação, migração e diferenciação dos precursores neurais do sistema nervoso pós-natal de camundongos (Mus musculus)." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/138960.
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No final dos anos 60, os experimentos em proliferação celular anunciaram a neurogênese adulta em mamíferos. Três décadas depois a relação entre neurogênese e células-tronco neurais (NSCs) foi estabelecida. Atualmente, as NSCs são objeto de pesquisas na medicina como modelo de estudo de múltiplos estados anormais e distúrbios orgânicos, além de se propor como uma estratégia em condições com poucas alternativas terapêuticas. Contudo o desenvolvimento destas terapias depende do entendimento dos mecanismos moleculares, celulares e biológicos que controlam a neurogênese e as NSCs. Assim, o objetivo deste trabalho foi o estudo das teorias no funcionamento dos nichos neurogênicos e as NSCs com ênfase na proliferação, migração e diferenciação, além da descrição dos aspectos celulares in vitro dos precursores neurais (NPCs) dos nichos neurogênicos dos mamíferos. Os nichos são regiões do sistema nervoso adulto que apresentam neurogênese pela presença das NSCs e um microambiente celular apropriado. Nos mamíferos existem pelo menos dois nichos, a zona subventricular (SVZ) dos ventrículos laterais e a zona subgranular (SGZ) do hipocampo. Os estudos revisados demostram que existem diferenças e semelhanças no comportamento das NSCs nos nichos neurogênicos adultos, levando a que a proliferação, migração e diferenciação seja menos efetiva quando comparada com o desenvolvimento embrionário. Para finalizar, se descreveu o protocolo para isolamento e cultivo dos NPCs e seus aspectos celulares. Os NPCs proliferaram como populações heterogêneas multipotentes. Após a diferenciação, as células migraram e apresentaram características morfológicas e imunofenotípicas de células neurais imaturas, com o predomínio de células gliais. Em conjunto, os NPCs in vitro mimetizam os aspectos gerais da neurogênese.
In the late 60`s, the experiments on cell proliferation announced adult neurogenesis in mammals. Three decades later, the link between neurogenesis and neural stem cells (NSCs) was recognized. Currently, NSCs are the matter of research in human and veterinary medicine as a model of multiple abnormal states and organic disorders, in addition to be proposed as a strategy for diseases and conditions with few therapeutic alternatives. However, the successful development of these therapies depends on the understanding of molecular, cellular and biological mechanisms that control neurogenesis and NSCs. Therefore, the aim of this work was the study of the theories on neurogenic niches and NSCs with focus in proliferation, migration and differentiation, beyond the description of the cellular aspects of in vitro neural precursors cells (NPCs) of the neurogenic niches of the mammals. The neurogenic niches are regions of the adult nervous system which display complete neurogenesis because of the presence of NSCs and an appropriate cell microenvironment. In mammals, there are at least two neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. The reviewed studies showed that exists differences and similarities in the behavior of the adult NSCs in the neurogenic niches that lead to less effective proliferation, migration and differentiation; when compared with the embryonic development. Finally, was described the protocol for isolation and cultivation of NPCs and their cellular aspects. NPCs proliferated as heterogeneous multipotent populations. Differentiation analyses showed that cells migrated and showed morphological and immunophenotypical characteristics of immature cells with the predominance of glial cells. Overall, NPCs effectively reproduce the general aspects of neurogenesis.
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Stermann, Alexander. "MYCN-DNA-Vakzine zur Behandlung des Neuroblastoms." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2014. http://dx.doi.org/10.18452/16888.
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Das Neuroblastom (NB) zählt zu den therapieresistentesten Tumoren des Kleinkindalters. Besonders NB-Patienten mit MYCN-Amplifikation sind mit einer schlechten Prognose konfrontiert. Neuere Studien legen nahe, dass eine spezifische aktive Immuntherapie gegen MYCN ein vielversprechender Ansatz zur Bekämpfung dieser malignen Erkrankung darstellen könnte. Zur Untersuchung dieser Hypothese wurde ein sogenanntes Minigen-Vakzin, welches für drei ausgewählte Epitope aus der MYCN-AS-Sequenz kodiert, generiert. Die Auswahl der Minigen-Epitope erfolgte mit dem MHC-Liganden-Vorhersageprogramm syfpeithi, welches drei starke H2-Kk-Liganden lieferte. Außerdem wurden zwei weitere Vakzine hergestellt: als Negativkontrolle MYCNLow, dessen MYCN-Peptide laut syfpeithi schlechte MHC-Klasse-I-Liganden darstellen und ein cDNA-Vakzin auf Basis der gesamten MYCN-cDNA-Sequenz. Zur Applikation der Vakzine wurden attenuierte Salmonella typhimurium SL7207 verwendet, die eine zusätzliche Stimulierung des mukosalen Immunsystems hervorrufen. Für die Untersuchung der Impfstoffe in vivo wurden zwei neuartige immunkompetente NB-Mausmodelle etabliert. Dazu wurden die syngenen NXS2/C1300 A/J-Mausmodelle soweit modifiziert, dass sie über eine induzierbare MYCN-Expression verfügten. Nach Auswahl und Charakterisierung geeigneter Transfektanten in vitro und in vivo wurde in diesen Modellen die Wirksamkeit der Vakzine untersucht. In diesen Versuchen konnte mit Hilfe der Vakzine das Primärtumorwachstum von NXS2-MYCN in geimpften Tieren signifikant im Vergleich zu Kontrollen reduziert und die Metastasierung durch C1300-MYCN Zellen signifikant verzögert werden. Mit den in-vivo-Versuchen anschließenden Analysen wurde schließlich bewiesen, dass die Immunantwort durch tumorinfiltrierende MYCN-spezifische zytotoxische CD8+ T-Zellen vermittelt wird. Zusammenfassend konnte gezeigt werden, dass eine MYCN-DNA-Vakzinierung erfolgreich zur Behandlungen MYCN-exprimierender NB im Mausmodell eingesetzt werden kann.High-level expression of MYCN protein caused by amplification of the gene characterizes a malignant phenotype of neuroblastoma (NB). Recent studies suggest that MYCN might be a promising target for immunotherapy. Therefore, we investigated the efficacy of three MYCN-specific DNA vaccines. Two minigene vaccines were generated; each encoded for three selected epitopes of the MYCN protein sequence with the highest, or as a control lowest, predicted affinity to MHC-Class-I Molecules. The third vaccine based on the cDNA of MYCN. Salmonella typhimurium SL7207 were used as oral application vehicle for the vaccines in in vivo experiments to induce an additional stimulation of the immune system. To investigate the immunotherapeutic approach NXS2- and C1300-cells syngeneic to immunocompetent A/J-mice were stably transfected with a tetracycline inducible vector system coding for MYCN. The transfectants were characterized and established in vitro and in vivo. In the MYCN-overexpressing models vaccination with the MYCN-DNA-vaccines resulted in significant reduced primary tumor growth or decelerated metastasis spread. The immune responses in the in vivo experiments followed by orally applied MYCN-DNA vaccines was mediated by tumor infiltrating cytotoxic CD8+ and CD4+ T cells. MYCN specificity of infiltrating lymphocytes was verified by MYCN-specific cytolytic activity and IFN-gamma secretion ex vivo. Finally, we showed that blocking of MHC-class I molecule H2-Kk approbated cytotoxicity mediated by CD8+ T cells, indicating MYCN specificity of the induced immune response. In summary, we showed that a MYCN based DNA vaccination strategy is effective against MYCN-expressing NB in vivo. In light of the description of MYCN-specific T cells in NB patients, the lytic action of autologous T cells on MYCN-expressing cells and the results of this study underline the possible potential of an active immunotherapy against MYCN as an alternative therapeutic approach to treat NB.
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Delgado-Garcia, Lina Maria. "Estudo da proliferação, migração e diferenciação dos precursores neurais do sistema nervoso pós-natal de camundongos (Mus musculus)." Botucatu, 2016. http://hdl.handle.net/11449/138960.
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Orientador: Rogério Martins AmorimResumo: No final dos anos 60, os experimentos em proliferação celular anunciaram a neurogênese adulta em mamíferos. Três décadas depois a relação entre neurogênese e células-tronco neurais (NSCs) foi estabelecida. Atualmente, as NSCs são objeto de pesquisas na medicina como modelo de estudo de múltiplos estados anormais e distúrbios orgânicos, além de se propor como uma estratégia em condições com poucas alternativas terapêuticas. Contudo o desenvolvimento destas terapias depende do entendimento dos mecanismos moleculares, celulares e biológicos que controlam a neurogênese e as NSCs. Assim, o objetivo deste trabalho foi o estudo das teorias no funcionamento dos nichos neurogênicos e as NSCs com ênfase na proliferação, migração e diferenciação, além da descrição dos aspectos celulares in vitro dos precursores neurais (NPCs) dos nichos neurogênicos dos mamíferos. Os nichos são regiões do sistema nervoso adulto que apresentam neurogênese pela presença das NSCs e um microambiente celular apropriado. Nos mamíferos existem pelo menos dois nichos, a zona subventricular (SVZ) dos ventrículos laterais e a zona subgranular (SGZ) do hipocampo. Os estudos revisados demostram que existem diferenças e semelhanças no comportamento das NSCs nos nichos neurogênicos adultos, levando a que a proliferação, migração e diferenciação seja menos efetiva quando comparada com o desenvolvimento embrionário. Para finalizar, se descreveu o protocolo para isolamento e cultivo dos NPCs e seus aspectos celulares. O... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: In the late 60`s, the experiments on cell proliferation announced adult neurogenesis in mammals. Three decades later, the link between neurogenesis and neural stem cells (NSCs) was recognized. Currently, NSCs are the matter of research in human and veterinary medicine as a model of multiple abnormal states and organic disorders, in addition to be proposed as a strategy for diseases and conditions with few therapeutic alternatives. However, the successful development of these therapies depends on the understanding of molecular, cellular and biological mechanisms that control neurogenesis and NSCs. Therefore, the aim of this work was the study of the theories on neurogenic niches and NSCs with focus in proliferation, migration and differentiation, beyond the description of the cellular aspects of in vitro neural precursors cells (NPCs) of the neurogenic niches of the mammals. The neurogenic niches are regions of the adult nervous system which display complete neurogenesis because of the presence of NSCs and an appropriate cell microenvironment. In mammals, there are at least two neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. The reviewed studies showed that exists differences and similarities in the behavior of the adult NSCs in the neurogenic niches that lead to less effective proliferation, migration and differentiation; when compared with the embryonic development. Finally, was described the proto... (Complete abstract click electronic access below)
Mestre
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Chell, James Michael. "Toward an understanding of Drosophila neuroblast reactivation." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608657.
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Beutenmüller, Ute Susanne [Verfasser]. "Vergleich des Transkriptoms mikrodissezierter Neuroblastome mit fetalen Neuroblasten / Ute Susanne Beutenmüller." Köln : Deutsche Zentralbibliothek für Medizin, 2014. http://d-nb.info/1058009672/34.
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Langer, Diana. "Identification of Miranda Associated Proteins and RNA in Drosophila melanogaster Neuroblasts." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-106757.
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Walsh, Kathleen. "Drosophila Embryonic Type II Neuroblasts: Origin, Temporal Patterning and Contribution to the Adult Central Complex." Thesis, University of Oregon, 2018. http://hdl.handle.net/1794/23150.
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The large numbers of neurons that comprise the adult brain display an immense diversity. Repeated divisions of a relatively small pool of neural stem cells generate this neuronal diversity during development. To increase progress towards medical treatments for neurodegenerative diseases, it is of interest to understand both how neural stem cells generate the assortment of neurons and how these neurons come together to form a functional brain. Brain assembly occurs sequentially across time with early events laying the foundation for later events. Drosophila neural stem cells, neuroblasts (NBs), are an excellent model for investigating how neural diversity is generated and what roles early and late born neurons have in shaping the stereotypical adult brain structure. Generation of neural diversity, begins with specifying the diverse population of stem cells, called spatial patterning, and continues with diversifying neurons made from the diverse stem cells, called temporal patterning. Drosophila NBs exhibit both spatial and temporal patterning. Drosophila NBs have three types of division modes: type 0, type I and type II. Type II NBs expand the number of neurons made with progeny that exhibit a transit-amplifying division pattern, similar to that of mammalian outer subventricular zone (OSVZ) progenitors. Additionally, type II NBs exhibit temporal patterning across both the NB and their progeny to generate a large diversity of neurons that populate a conserved region of the brain responsible for many sensory and motor functions, called the central complex.
Type II NBs have only been identified and studied during later stages in development, with nothing known about their origin or early divisions. In this dissertation, I describe the early lineages of the type II NBs within the Drosophila embryo. I show that type II NBs and lineages originate early in development, exhibit temporal patterning across both the NB and transit-amplifying progeny, and produce neurons that survive into the adult brain to innervate and potentially serve as a foundation within the adult central complex. Additionally, I explain how live imaging of the developing Drosophila brain can answer questions not easily addressed through other methods.
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Müller, Ines [Verfasser]. "Oberflächenmodifizierte Arsentrioxid-Liposomen für die Neuroblastom-Therapie / Ines Müller." München : Verlag Dr. Hut, 2013. http://d-nb.info/1037286782/34.
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Leclair, Marc-David Héloury Yves Rozé Jean-Christophe. "Place de la chirurgie dans les neuroblastomes de l'enfant." [S.l.] : [s.n.], 2008. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=50991.
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Skowron, Matthias Raphael [Verfasser]. "Analyse stadiumspezifisch exprimierter Gene im Neuroblastom / Matthias Raphael Skowron." Köln : Deutsche Zentralbibliothek für Medizin, 2009. http://d-nb.info/99930478X/34.
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Classe, Marion. "Génomique intégrée des neuroblastomes olfactifs : implications anatomopathologiques et thérapeutiques." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066459/document.
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Les neuroblastomes olfactifs (NBOs) sont des tumeurs rares de la base du crâne. Les outils de classification de ces tumeurs sont insuffisants, il n’existe notamment aucune classification moléculaire des NBO. La biologie de ses tumeurs est mal connue. Nos travaux se sont appuyés sur l’analyse des exomes, du transcriptome, du méthylome et des caractéristiques histopathologiques et immunitaires d’une série de 59 NBOs bien annotés cliniquement. Nous avons mis en évidence l’existence de 2 sous-types de NBO présentant un profil d’expression et un profil anatomo-clinique différent. Le type neural, correspond à une tumeur bien différenciée, peu agressive, présentant des caractéristiques plutôt neuronales et partageant des caractéristiques phénotypiques avec les progéniteurs directs de neurones olfactifs. Le type basal correspond à une tumeur moins différenciée, plus agressive, ayant des caractéristiques plutôt embryonnaires, partageant des caractéristiques phénotypiques avec les cellules basales de renouvellement de l’épithélium olfactif. Nous avons mis en évidence que la charge mutationnelle était plus élevée dans le type basal, avec notamment des mutations IDH2 R172 récurrentes, associées à un phénotype CpG Island Methylator (CIMP). Nous avons également montré que les NBOs de type basal étaient infiltrés par un nombre plus important de lymphocytes T avec, dans certaines tumeurs, une expression plus marquée de checkpoints immunitaires et de facteurs immunosuppresseurs. Ce travail ouvre la perspective d’une classification moléculaire permettant de mieux stratifier les patients et ouvre également le champ de nouvelles stratégies thérapeutiques dans ces tumeurs raresOlfactory neuroblastomas (ONBs) are rare tumors arising in the skull base. Classification tools are poor, notably; no molecular classification of ONB has been reported. Literature data about their cell of origin, the existence of molecular therapeutic targets or their immune environment being scarce, the biology of these tumors is still poorly understood. Our work was based on exome, transcriptome and methylome analysis, but also on histopathological and immune characteristics of a series of 59 clinically well annotated ONBs. We highlighted 2 sub-types of ONB showing different expression and clinicopathologic patterns. The neural type is a well differentiated, poorly aggressive tumor which shows neurons characteristics and shares phenotypic similarities with olfactory neuron progenitors. The basal type is a less differentiated tumor, displaying an aggressive phenotype, with embryonic phenotypical characteristics, which shares similarities with basal renewing cells of the olfactory epithelium. We showed that the mutational load was higher in basal tumors, with notably recurrent IDH2 R172 mutations associated with a CpG Island Methylator Phenotype (CIMP). We also showed that basal type ONBs were infiltrated by a greater number of T cells with, in some cases, a higher expression of immune checkpoints and immunosuppressive factors. This work paves the way towards a new molecular classification which will allow a better stratification of patients and will open the field of new therapeutic strategies for this rare tumor
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Hoene, Victoria Sophie. "Die Rolle des Transkriptionsfaktors GATA-4 im humanen Neuroblastom." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16188.
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Das Neuroblastom, ein embryonaler Tumor des sympathischen Nervensystems, stellt durch seine außerordentliche Heterogenität klinisch eine große Herausforderung dar. Ziel dieser Arbeit war es, die Expression der GATA-Transkriptionsfaktoren GATA-2, -3, -4 und des Kofaktors friend-of-GATA (FOG)-2 im Neuroblastom und im sich entwickelnden sympathischen Nervensystem zu vergleichen. Davon ausgehend wurde die Rolle der Proteine im Neuroblastom näher untersucht. Es wurde gezeigt, dass alle vier Proteine in humanem Neuroblastom-Gewebe sowie in einer humanen Neuroblastom-Zelllinie (SH-SY5Y) exprimiert werden und nukleär lokalisiert sind. Lediglich Gata-4 wurde jedoch im sich entwickelnden sympathischen Nervensystem der Maus nicht exprimiert. Die Einzigartigkeit von GATA-4 bestätigte sich auch durch Microarray-Analysen von 251 Neuroblastom-Proben. Während GATA-2, -3 und FOG-2 signifikant mit Markern für eine günstige Prognose assoziiert wurden, korrelierte die GATA-4 Expression mit MYCN-Amplifikation. Interessanterweise führte die lentivirale Überexpression von GATA-4 zu einer Proliferationsinhibition humaner Neuroblastomzellen (SH-SY5Y und SH-EP) sowie zu der verstärkten Expression von DPYSL3 und Bcl-2. Zudem konnte durch das Differenzierungsagens Retinsäure die GATA-4 Expression induziert werden. So wurde in dieser Arbeit bestätigt, dass normale Entwicklungsprozesse in prognostisch günstigen Neuroblastomen intakt sind. Umgekehrt sind in Tumoren mit schlechterer Prognose diese Prozesse gestört. Die in vitro verlangsamte Proliferation sowie die Induktion von Bcl-2 nach Überexpression von GATA-4 könnten in vivo bei der schlechteren Therapierbarkeit der prognostisch ungünstigen Neuroblastome eine Rolle spielen. Es ist bekannt, dass die Behandlung mit Retinsäure u. a. durch Bcl-2 zu einer Chemoresistenz führen kann. Da die Expression von GATA-4 durch Retinsäure induziert werden und GATA-4 die Expression von Bcl-2 verstärken kann, könnte GATA-4 an der Chemoresistenz beteiligt sein.Neuroblastoma, an embryonal tumor of the sympathetic nervous system, remains clinically challenging due to its extreme heterogeneity. The aim of this study was to compare the expression of GATA transcription factors GATA-2, -3, -4 and the cofactor friend-of-GATA (FOG)-2 in neuroblastoma and in the developing sympathetic nervous system. The functional role of these proteins in neuroblastoma was subsequently investigated based on the results of the GATA expression studies. The analysis showed that all four proteins are expressed in human neuroblastoma tissue as well as in a human neuroblastoma cell line (SH-SY5Y) and are localized in the cell nuclei. Only Gata-4, however, was not expressed in the developing murine sympathetic nervous system. Its uniqueness was also confirmed by microarray analyses of 251 neuroblastoma specimens. While GATA-2, -3 and FOG-2 were significantly associated with favorable prognostic markers, GATA-4 expression correlated with MYCN-amplification. Interestingly, lentiviral GATA-4 overexpression led to inhibited proliferation of human neuroblastoma cells (SH-SY5Y and SH-EP) as well as to increased expression of DPYSL3 and Bcl-2. In addition, GATA-4 expression could be induced by the differentiation agent retinoic acid. In conclusion, it was confirmed that normal developmental molecular pathways are intact in prognostically favorable neuroblastoma. In contrast, these developmental processes seem to be defective in tumors with unfavorable prognosis. The slowed proliferation, as observed in vitro, as well as the induction of Bcl-2 brought about by GATA-4 overexpression may contribute in vivo to the difficult treatability of prognostically unfavorable neuroblastoma. It is known that treatment of neuroblastoma with retinoic acid can lead to chemoresistance, mediated by Bcl-2 amongst others. Since retinoic acid can induce the expression of GATA-4 and GATA-4 itself can enhance the expression of Bcl-2, GATA-4 could be involved in chemoresistance.
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Leclair, Marc-David. "Place de la chirurgie dans les neuroblastomes de l'enfant." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=008bc478-2fa0-4298-9600-997d5627727f.
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Le neuroblastome est une tumeur maligne de l'enfant qui est caractérisée par une très grande hétérogénéité clinique, d'une maladie presque bénigne à une maladie presque incurable. Les facteurs pronostiques qui expliquent cette variabilité sont dominés par l'âge, le stade, et un ensemble de caractéristiques biologiques, qui permettent le regroupement des neuroblastomes en groupes de risque similaire, qui conditionnent des stratégies thérapeutiques différentes. La chirurgie du neuroblastome doit prendre en compte ces variables. Dans ce travail, nous réalisons l��analyse de la balance entre le bénéfice oncologique d’une exérèse complète et le risque de complications dans une localisation particulière de neuroblastome où le risque de séquelles fonctionnelles est important (le neuroblastome pelvien), et nous étudions l’intérêt de la chirurgie mini-invasive dans les tumeurs solides de l’enfant, avec une évaluation de l’efficacité de la laparoscopie dans les neuroblastomes abdominaux. Ces travaux apportent un éclairage particulier sur le rôle de la chirurgie dans la prise en charge de cette tumeur maligne complexe : Si la nécessité de la chirurgie est bien établie et que la qualité de l’exérèse semble importante, les bénéfices d’une exérèse complète sont à mettre en balance avec les risques de complications et de séquelles postopératoires. La question des séquelles se pose d’autant plus qu'il s’agit de tumeurs localisées, survenant chez des nourrissons où l'on connaît les possibilités de régression ou de maturation spontanée de la tumeur. Dans ce sous-groupe, l'excellente survie conduit à élaborer des stratégies de désescalade thérapeutique dans lesquelles la chirurgie a un rôle à jouer. La réduction de la toxicité du traitement passe aussi par une diminution du poids de la chirurgie, et le développement de techniques innovantes est un élément qui y participeNeuroblastoma is a malignant pediatric tumour characterized by a wide clinical heterogeneity, from an almost benign to an almost incurable disease. Prognostic factors accounting for this variability include age, stage, and biological characteristics, and allow distribution of neuroblastoma in different risk groups with corresponding treatment strategies. Surgery of neuroblastoma has to take these variables into account. In the present work, we study the balance between oncological benefit of a complete resection and the risk of complications in a site of neuroblastoma with a high risk of neurological sequellae (pelvic neuroblastoma), and we report the use of minimally-invasive techniques with a series of children with abdominal neuroblastoma resected laparoscopically. These studies contribute to clarify the role of surgery in the treatment of this complex malignant disease : If the need for surgery is well established and if the extent of resection is important for cure, the benefits of resection need to be balanced with the risk of complications and postoperative sequellae, especially in infants in whom localized and even metastatic neuroblastomas have a potential for maturation or spontaneous regression. In this subgroup with an excellent survival, surgery and innovating minimally invasive techniques may contribute to decrease the burden of treatment
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Pearson, Bret James. "Regulation of temporal identity in Drosophila neuroblast lineages /." view abstract or download file of text, 2005. http://wwwlib.umi.com/cr/uoregon/fullcit?p3164084.
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Thesis (Ph. D.)--University of Oregon, 2005.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 152-164). Also available for download via the World Wide Web; free to University of Oregon users.
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RIZZO, ILARIA MARIA. "Biological role of sphingosine 1-phosphate in neuroblasts derived from otic vesicle." Doctoral thesis, Università di Siena, 2016. http://hdl.handle.net/11365/1009811.
Full textAbstract:
Hearing loss is a health and social problem, particularly common among older people. Deafness is
associated with an irreversible loss of sensory hair cells and spiral ganglion neurons, which don’t
have regenerative potential. To date, cochlear implants are the only possible therapy, even if not
always effective. Therefore, there is an enormous research interest aimed at identifying factors that
could prevent hearing loss.
Sphingosine 1-phosphate (S1P) is a bioactive lipid involved in the regulation of many physiological
and pathological processes. Most of S1P functions are mediated through a family of five G-protein
coupled receptors. Cytokines and growth factors cross-talk with S1P pathway via the regulation of
the expression levels and activity of the enzymes responsible for S1P production, sphingosine kinases
(SK1 and SK2), and S1P receptors (S1P1-5) in different cellular types.
Recently, a crucial role for S1P signaling axis has been demonstrated in hearing loss. S1P receptor 2
(S1p2) and Spinster-2 (Spns2, the S1P specific transporter) knock-out mice are deaf for defects in the
stria vascularis. Nevertheless, the exact role of S1P in sensory hair cells and spiral ganglion neurons
biology has not been clarified.
In this study, the mouse otocyst cell line US/VOT-N33 has been used as experimental model of
differentiation into neurons of the spiral ganglion. We have demonstrated that fibroblast growth
factor 2 (FGF2) was able to induce the proliferation of US/VOT-N33 and to act as pro-survival factor
in staurosporine-induced apoptosis. Moreover, SK1 and SK2 are required for FGF2-mediated
proliferation and cell survival, measured by 3HThymidine incorporation and caspase-3
activity/cleavage assay respectively, demonstrating an involvement of S1P signaling axis in these
effects. While S1P1 and S1P2 down-regulation affects proliferation, S1P receptor activation is not
required for cell survival induced by FGF2. Additionally, the ERK1/2 MAPK signaling pathway was
found to mediate the mitogenic action of FGF2.
The cell counting of neurite-bearing cells and Western blotting analysis for Islet1/2 neuronal marker
were performed to evaluate FGF2-induced neuronal differentiation of this cell line. Preliminary
results showed that this effect exerted by FGF2 was reduced by concomitant addition of exogenous
S1P. Furthermore, pro-differentiating role exerted by FGF2 was increased in presence of SK1
knockdown and when SPNS2 is silenced, presuming a negative role of S1P pathway in FGF2-induced
neuritogenesis.
Taken together, these findings demonstrate a crucial role for S1P signaling axis in proliferation and
survival of otic vesicle neuroprogenitors, however further studies will be necessary in order to clarify
the role of S1P pathway during the differentiation of the spiral ganglion neurons.
This work could help to identify possible novel therapeutical approaches to prevent neuronal
degeneration during hearing loss.
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Caussinus, Emmanuel. "Croissances tumorales induites par l'altération des divisions asymétriques de cellules souches chez la Drosphile." Toulouse 3, 2005. http://www.theses.fr/2005TOU30208.
Full textAbstract:
Il existe une forte corrélation entre perte de polarité des cellules épithéliales et carcinome. Toutefois, la relation de cause à effet reste à découvrir. Dans les cellules souches, la perte de polarité cellulaire et les anomalies de division asymétrique qui en découlent pourraient entraîner des défauts de différenciation cellulaire. Ces anomalies seraient capables d'empêcher la descendance des cellules souches de répondre aux mécanismes qui contrôlent normalement la prolifération cellulaire. Pour tester cette hypothèse, nous avons généré dans la larve de Drosophile des neuroblastes portant des mutations dans différents gènes qui contrôlent la division asymétrique de ces cellules. Nous avons testé le potentiel prolifératif de ces neuroblastes en les transplantant dans des hôtes adultes. Nos résultats montrent que des morceaux de cerveaux de larve comportant des neuroblastes dont les gènes pins, mira, numb ou pros sont mutés peuvent grossir plus de cent fois dans l'hôte. Ces tumeurs envahissent les organes de l'hôte, le tuant en moins de trois semaines. Ces tumeurs deviennent immortelles et peuvent être retransplantées pendant des années. L'instabilité génomique et l'altération des centrosomes, deux caractéristiques fréquentes des carcinomes, n'existent pas dans la phase d'initiation de ces tumeurs. Pourtant, six semaines après la première transplantation, ces deux traits particuliers des carcinomes affectent plus de 10% des cellules tumorales. De nombreux travaux suggèrent que certains cancers pourraient provenir de cellules souches malignes. Nos résultats montrent que la perte de fonction d'un seul gène parmi plusieurs gènes qui contrôlent la différenciation de la descendance des cellules souches peut entraîner une prolifération incontrôlée de ces lignées cellulaires, déclenchant une chaîne d'événements qui dérèglent l'homéostasie cellulaire au sens large et peut conduire au cancerLoss of cell polarity and cancer are tightly correlated, but a causative relationship has remained elusive. In stem cells, polarity loss and the resulting impairment of asymmetric cell division could bring about cell-fate alterations that could render one or the two daughters unable to respond to the mechanisms that control proliferation in the wild-type lineage. To test this hypothesis we have generated Drosophila larval neuroblasts that are mutant for different genes that control the asymmetric cell-division machinery and assayed their proliferative potential upon transplantation into adult hosts. We have found that pieces of larval brains carrying pins, mira, numb or pros mutant neuroblasts can grow over a hundred-fold the size of the implant, invading other tissues, and killing the hosts in less than three weeks. These tumors become immortal and can be re-transplanted into new hosts for years. Genome instability and centrosome alterations, two frequent traits of malignant carcinomas, are kept at wild-type levels during the initial stages of development in these tumors. However, six weeks after the first transplantation they affect at least 10% of the cells in all tumor lines. Growing evidence strongly suggests that the origin of some tumors may be a cancerogenic stem cell. Our results show that loss of function of any single one of several genes that control the cell-fate asymmetry of stem-cells daughters may result in over-proliferation of this lineage, triggering a chain of events that subverts cell homeostasis in a very general sense, and leads to cancer
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Hübener, Nicole. "DNA-Vakzinierung mit Tyrosinhydroxylase-Impfstoffen zur aktiven Immuntherapie des Neuroblastoms." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2007. http://dx.doi.org/10.18452/15675.
Full textAbstract:
Das Neuroblastom ist der am weitesten verbreitete solide, extrakranielle Tumor im Kindesalter. Trotz intensiver Forschung sind die Überlebensraten von Patienten mit fortgeschrittenem Tumorwachstum nach wie vor schlecht. Die Idee, eine zelluläre, langanhaltende Immunantwort im Körper zu induzieren, vermittelt durch zytotoxische CD8+T-Zellen, die sich gegen den Tumor richten, scheint dabei besonders attraktiv. Als tumorassoziiertes Antigen (TAA) wurde zu diesem Zweck für diese Arbeit die murine Tyrosinhydroxylase (mTH), das Schrittmacherenzym der Katecholaminbiosynthese, gewählt, da sie in der Mehrzahl der Neuroblastome stark überexprimiert ist. Für die Impfexperimente wurden sog. DNA-Minigen-Vakzine, die für Peptide aus der mTH-Sequenz kodieren, konstruiert. Die Auswahl Minigen-Peptide erfolgte mit dem MHC-Klasse-I-Liganden-Vorhersageprogramm syfpeithi, welches drei vorhergesagte starke H2-Kk-Liganden lieferte (mTH3k). Außerdem wurden zwei weitere Vakzine hergestellt: als Negativkontrolle das Vakzin mTHlowest, dessen mTH-Peptide laut syfpeithi schlechte MHC-Klasse-I-Liganden darstellen und das Vakzin Ersatzepis, dessen Peptide auf der Oberfläche von murinen NXS2-Neuroblastomzellen aus MHC-Klasse-I-Komplexen isoliert werden konnten. Sowohl in prophylaktischen als auch therapeutischen Impfversuchen in Mäusen konnte das Tumorwachstum und die spontane Metastasierung in sekundäre Organe wie die Leber signifikant verhindert werden. Außerdem konnte gezeigt werden, daß der Antitumoreffekt auf der Induktion mTH-spezifischer, zytotoxischer CD8+T Zellen (CTLs) beruht. Zusätzlich und insbesondere interessant für eine eventuelle klinische Anwendung eines auf der TH basierenden DNA-Vakzins verursachte das mTH-Minigen-Vakzin zumindest in Mäusen keine Aktivierung selbst-reaktiver CD8+T-Zellen. Alles in allem lassen die in dieser Arbeit erhaltenen Ergebnisse den Schluß zu, daß sich die Tyrosinhydroxylase als TAA in Form eines DNA-Vakzins zur adjuvanten Therapie des Neuroblastoms eignet.Therapeutic vaccination against tumor antigens without induction of autoimmunity remains a major challenge in cancer immunotherapy. Here, we demonstrate for the first time effective therapeutic vaccination followed by eradication of established spontaneous neuroblastoma metastases using a tyrosine hydroxylase (TH) DNA minigene vaccine. We identified three novel mouse TH (mTH3) derived peptides with high predicted binding affinity to MHC class I H2-Kk according to prediction program syfpeithi and computer modeling of epitopes into MHC class I binding groove. Subsequently, a DNA minigene vaccine based on pCMV-F3Ub encoding for mutated ubiquitin (G76 to A76) and mTH3 was generated. Prophylactic and therapeutic efficacy of this vaccine was established following oral delivery using attenuated Salmonella typhimurium SL7207. Only mice immunized with mTH3 were free of spontaneous liver metastases. This effect was clearly dependant on ubiquitin and high affinity of the mTH epitopes to MHC class I. Specifically, we demonstrated a crucial role for minigene expression as a stable ubiquitin-Ala76 fusion peptide for vaccine efficacy. Interestingly, the unstable wild type ubiquitin-Gly76 vaccine was completely ineffective. The immune response following mTH3 DNA minigene vaccination was mediated by CD8+ T-cells as indicated by infiltration of primary tumors and TH specific cytolytic activity in vitro. Importantly, no infiltration was detectable in TH expressing adrenal medulla, indicating the absence of auto immunity. In summary, we demonstrate effective therapeutic vaccination against neuroblastoma with a novel rationally designed tyrosine hydroxylase minigene vaccine without induction of autoimmunity providing an important base line for clinical application of this strategy.
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ROY, ANNIE. "Correlations anatomoradiologiques dans 26 cas de neuroblastomes operes chez l'enfant." Toulouse 3, 1993. http://www.theses.fr/1993TOU31529.
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Siegrist, Sarah Elizabeth. "Extrinsic and intrinsic cues polarize the Drosophila neuroblast cortex /." view abstract or download file of text, 2005. http://www.lib.umi.com/cr/uoregon/fullcit?p3201698.
Full textAbstract:
Thesis (Ph. D.)--University of Oregon, 2005.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 95-105). Also available for download via the World Wide Web; free to University of Oregon users.
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Pendred, Julia. "A screen for genes regulating neuroblast activity in Drosophila." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445007/.
Full textAbstract:
Following embryogenesis, the morphology of the CNS becomes dramatically remodelled to reflect the different locomotive and sensory requirements of the adult relative to the larva. This is largely achieved through the varying spatio-temporal proliferation patterns of the neural stem cell-like precursors (termed postembryonic neuroblasts: pNBs). Although both NB-autonomous and non-cell autonomous mechanisms have been identified, relatively few factors controlling this process are known. My studies focus on using genetic screening to identify new genes involved in this process. I executed two genetic screens, which were designed to complement each others limitations. The first of these involved screening using Mosaic Analysis with a Repressible Cell Marker (MARCM), to identify embryonic-lethal mutations that act in a cell-autonomous manner to produce under- or over-sized pNB clones. The second screen focused on the rarer class of pupal-lethal mutation, where homozygous mutant larvae were screened for abnormal morphology of the CNS. In total, we screened 4200 mutagenised lines on chromosome III, recovering 82 mutants with interesting phenotypes 68 from the MARCM screen and 14 from the pupal-lethal screen. These were divided into 69 complementation groups, 9 of which contained multiple alleles. These groups were subdivided into phenotypic classes, with 9 distinct classes recovered from the MARCM screen and 2 from the pupal-lethal screen. These were sub-categorised into CNS-specific or non-CNS specific, according to the absence or presence of a phenotype in the eye disc. I initially focused my studies on 9 of the pupal-lethal mutations, 5 of which I successfully mapped using chromosomal deficiencies, to 38-329Kb intervals. Two mutations showing undersized brain lobes, juvenile at mid-third instar (jami) and reduced optic and imaginal expansion (roie) were selected for detailed molecular and genetic analysis and comparison. Both genes are required in differing region- and stage-specific manners throughout the CNS. jami positively regulates CNS growth by both non-cell autonomous and cell-autonomous mechanisms, according to the region and stage. In contrast roie promotes growth in a strictly cell-autonomous manner with a strong requirement in symmetrically dividing precursors. Using deficiencies, jami was fine-mapped to a region containing 5 genes and one strong candidate gene for roie, CGI3074, was identified by P-element mediated recombination mapping combined with genetic techniques and available Drosophila database resources.
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Gajendra, Sangeetha. "Molecular regulation of neuroblast migration in the postnatal brain." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/molecular-regulation-of-neuroblast-migration-in-the-postnatal-brain(055c4407-fb25-436a-91f6-e5fdf2fb42d1).html.
Full textAbstract:
The subventricular zone (SVZ) is one of the main neurogenic niches in the postnatal brain. Neural precursors derived from SVZ stem cells migrate in chains to the olfactory bulb (OB) via the rostral migratory stream (RMS) through channels (glial tubes) formed by the processes of astrocytes. Importantly, these precursors have the capacity to migrate away from their native route to areas of pathological damage in the adult brain. Therefore, studying the migratory properties of these cells is essential, not only to understand basic aspects of adult neurogenesis, but also to exploit the potential of adult neural stem cells in neuroregenerative strategies. Whilst considerable progress has been made in the field of SVZ neural precursor migration, the exact molecular mechanisms regulating this process remain to be fully elucidated. The endocannabinoid system is known to play an important role in the regulation of neural stem cell proliferation. Here, we show that CB signalling also regulates the migration of SVZ-derived neural precursors. In addition, stimulation of G-protein coupled cannabinoid receptors, CB1 and CB2, leads to significant activation of RalA, a Ras-like GTPase involved in the control of neuronal morphology and polarity. siRNA-mediated knockdown of RalA or the expression of dominant negative RalA abolished cannabinoid-induced stimulation of migration. Time-lapse imaging revealed that depletion of RalA strongly impaired nucleokinesis: a crucial step for efficient migration. Analysis of RalA function in vivo, using wild type and mutant constructs electroporated into the SVZ, showed that the loss of RalA function results in both altered morphology and direction of migration. Finally, selective deletion of RalA in RMS neuroblasts in vivo further confirms that RalA is required for correct polarised morphology of migrating neuroblasts in the RMS. In summary, RalA is activated by CB agonists, and is required for CB-promoted migration of RMS neuroblasts. Furthermore, RalA expression is necessary for polarised morphology and efficient migration of RMS neuroblasts both in vitro and in vivo.
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Nipper, Rick William. "Molecular function of the cell polarity protein Partner of Inscuteable in Drosophila neuroblasts /." Connect to title online (Scholars' Bank) Connect to title online (ProQuest), 2007. http://hdl.handle.net/1794/6194.
Full textAbstract:
Thesis (Ph. D.)--University of Oregon, 2007.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 45-48). Also available online in Scholars' Bank; and in ProQuest, free to University of Oregon users.
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Almeida, M. S. S. "The role of Notch and Grainyhead in the development of the postembryonic neuroblasts." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.595481.
Full textAbstract:
Postembryonic neuroblasts (pNBs) in the Drosophila larval CNS are considered to be neural stem cells production most of the neurons of the adult Drosophila central nervous system (CNS). The pNBs are derived from the embryonic neuroblasts (NBs). After a period of quiescence at the end of embryogenesis they reactivate during larval life and proliferate extensively for a limited period. The pNBs are able to self-review in each division and also to produce a precursor cell that will generate two postmitotic cells that fully differentiate at metamorphosis. Therefore, the pNBs provide a good model to investigate the mechanisms involved in the regulation of neural stem cells. The aim of this research was to investigate whether Notch signalling and the transcription factor Grainyhead have roles in regulating pNBs processes. Before investigating the regulation of the pNBs behaviour it was first necessary to characterise in more detail the characteristics of these cells and their progeny. Several genes that are expressed in the embryonic CNS were selected to further study. Among these I identified some factors that are expressed only in specific pNB lineages, such as Gsb-p and others that are expressed at a specific stage in all lineages such as Prospero. Based on their expression pattern it appears that Gsb-p is likely to perform a similar function in the larval CNS as in the embryo. In contrast the distribution of Prospero suggest different roles in the pNB lineages. The result was first that the Notch pathway is active in the pNBs, indicated by the expression of Notch target gene mg. However, the results obtained, using clonal analysis to manipulate Notch function in the pNB lineages, indicate that Notch does not have a role in maintaining the undifferentiated state of the pNBs or their proliferative state. In contrast to its function in vertebrate systems where it is able to regulate the uncommitted state of the neural progenitor cells. The analysis of grh mutant indicated that Grh has a role in regulating the proliferation and/or cell death of the pNBs.
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FERRANDIS, ERIC. "Etude de la regulation de l'expression du gene mdr1 dans le neuroblaste humain." Paris 6, 1993. http://www.theses.fr/1993PA066364.
Full textAbstract:
Tumeur embryonnaire du tissu sympathique, le neuroblaste (nb) est l'un des cancers pediatriques les plus frequents. Le nb metastatique, au pronostic generalement severe, est traite par chimiotherapie mais manifeste souvent une chimioresistance a laquelle sont associes des taux eleves de transcrit du gene mdr1, gene implique dans le phenomene de resistance multiple aux drogues (mdr). D'autre part, l'oncogene n-myc, qui code pour une proteine nucleaire agissant comme un facteur transcriptionnel, est frequemment active par amplification genique dans ces formes disseminees de la maladie. Cette these etudie la regulation de l'expression du gene mdr1 humain et la compare a celle de l'oncogene n-myc dans des neuroblastes humains differencies, proliferatifs et metastatiques
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Nipper, Rick William Jr 1978. "Molecular function of the cell polarity protein partner of inscuteable in Drosophila neuroblasts." Thesis, University of Oregon, 2007. http://hdl.handle.net/1794/6194.
Full textAbstract:
xiii, 48 p. : (col. ill.) A print copy of this title is available through the UO Libraries under the call number: SCIENCE QL537.D76 N57 2007Asymmetric cell division (ACD) is a unique mechanism employed during development to achieve cellular diversity from a small number of progenitor cells. Cells undergoing ACD distribute factors for self-renewal at the apical cortex and factors for differentiation at the basal cortex. It is critical for proper development that the mitotic spindle be tightly coupled to this axis of polarization such that both sets of proteins are exclusively segregated into the daughter cells. We use ACD in Drosophila neuroblasts as a model system for understanding the molecular mechanisms that govern spindle-cortical coupling. Neuroblasts polarize Partner of Inscuteable (Pins), Gαi and Mushroom Body Defect (Mud) at the apical cell cortex during mitosis. Gαi and Pins are required for establishing cortical polarity while Mud is essential for spindle-cortical alignment. Gαi and Mud interact through Pins GoLoco domains and tetratricopeptide repeats (TPR) respectively, however it is unclear how Mud activity is integrated with Pins and Gαi to link neuroblast cortical polarity to the mitotic spindle. This dissertation describes how Pins interactions with Gαi and Mud regulate Iwo fundamental aspects of neuroblast ACD: cortical polarity and alignment of the spindle with the resulting polarity axis. I demonstrate that Pins is a dynamic scaffolding protein that undergoes a GoLoco-TPR intramolecular interaction, resulting in a conformation of Pins with low Mud and reduced Gαi binding affinity. However, Pins TPR domains fail to completely repress Gαi binding, as a single GoLoco is unaffected by the intramolecular isomerization. Gαi present at the apical cortex specifies Pins localization through binding this "unregulated" GoLoco. Liberation of Pins intramolecularly coupled state occurs through cooperative binding of Gαi and Mud to the other GoLoco and TPR domains, creating a high-affinity Gαi-Pins-Mud complex. This autoregulatory mechanism spatially confines the Pins-Mud interaction to the apical cortex and facilitates proper apical-spindle orientation. In conclusion, these results suggest Gαi induces multiple Pins states to both properly localize Pins and ensure tight coupling between apical polarity and mitotic spindle alignment.
Adviser: Ken Prehoda
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Mauser, Jonathon. "Regulatory Mechanisms Governing the Establishment of Cell Polarity and Mitotic Spindle Orientation in the Drosophila Neuroblast." Thesis, University of Oregon, 2014. http://hdl.handle.net/1794/18344.
Full textAbstract:
The Drosophila neuroblast undergoes repeated asymmetric cell divisions that produce one daughter cell that assumes a neuronal fate and another that remains a neuroblast. During mitosis, the neuroblast polarizes the conserved Par polarity complex to the apical cortex, which is responsible for segregating fate determinants to the basal cell cortex. Polarity is accompanied by orientation of the mitotic spindle through the proteins Pins, Mud, and Dlg to ensure that the cleavage furrow properly segregates the fate determinants. The adaptor protein Inscuteable coordinates these two pathways. In my work, I have addressed how asymmetrically dividing cells are dynamically polarized during the cell cycle and how the resulting polarity is coupled to spindle position.
To address how neuroblast polarity is dynamically controlled, I identified the protein Inscuteable as a continuously polarized cue for Par complex localization during mitosis. Inscuteable and Bazooka, a member of the Par complex, interact directly and form a complex that is regulated by the mitotic kinase Aurora A. Regulating this interaction allows for cell-cycle dependent establishment of polarity and for the subsequent loss of polarity after the cell divides.
To investigate how Par complex directed polarity is connected to spindle position, I investigated the effect of Inscuteable binding on the spindle orientation ability of the protein Pins. When bound to Inscuteable, Pins' spindle orientation activity becomes repressed. Inscuteable competes with Mud for Pins binding and represses the Gai-Pins-Mud signaling pathway. Function of the parallel Pins-Dlg pathway remains unaffected. This repression behavior may allow differential timing of spindle attachment (through Dlg) and spindle shortening (through Mud) pathways that ensures correct alignment of the mitotic spindle.
I was able to model the spindle orientation behavior of Pins using a synthetic protein containing activation sites that have different affinities for the activator. Changing the number and affinities of these activation sites leads to different response profiles that mimic the ultrasensitive behavior of Pins using a non-cooperative mechanism. Together, these regulatory mechanisms cooperate to allow for spatial and temporal control of polarity and for physical connection of polarity to the mitotic spindle.
This dissertation includes previously published and unpublished co-authored material.
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Fühlhuber, Verena. "Autoantikörper und deren pathogener Effekt auf neuronale Zellen beim kindlichen Opsoklonus-Myoklonus-Syndrom." Giessen : VVB Laufersweiler, 2008. http://d-nb.info/989048195/34.
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Layer, Julian Philipp [Verfasser]. "Die immunsuppressive Rolle von N-Myc im Neuroblastom / Julian Philipp Layer." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/117467119X/34.
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Varol, Emine [Verfasser], and Dietrich [Akademischer Betreuer] Kluth. "THY1-Expression im Neuroblastom als Prognosemarker / Emine Varol. Betreuer: Dietrich Kluth." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2013. http://d-nb.info/103878929X/34.
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Layer, Julian [Verfasser]. "Die immunsuppressive Rolle von N-Myc im Neuroblastom / Julian Philipp Layer." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/117467119X/34.
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Lagodny, Jeanette. "Regulation und Inhibition von Blut-Angiogenese und Lymph-Angiogenese im Neuroblastom." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:25-opus-50955.
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Drummond, Mike. "Spatial Regulation of the Polarity Protein aPKC During Asymmetric Cell Division of Drosophila Neuroblasts." Thesis, University of Oregon, 2015. http://hdl.handle.net/1794/19225.
Full textAbstract:
The Par complex protein, atypical protein kinase C (aPKC), plays an instrumental role in diverse cell polarities. aPKC is able to restrict substrate localization through a phosphorylation-induced cortical exclusion mechanism, allowing for the generation of molecularly distinct cortical domains. Thus, controlling the localization of aPKC is central to Par-mediated polarity but the mechanism by which aPKC is polarized remains poorly understood. In this dissertation I investigated the restriction of aPKC to the apical cortex of Drosophila neural stem cells, neuroblasts, as these cells dynamically polarize aPKC through repeated asymmetric cell divisions. The polarity created through aPKC phosphorylation must be tightly regulated in order to ensure proper balance between self-renewal and differentiation.
To begin, I investigated whether or not aPKC’s so called ‘maturation’ by PDK1 phosphorylation is required for aPKC activity and localization. We found that aPKC’s phosphorylation by PDK1 is required for both polarity and full activity. An aPKC containing an unphosphorylatable activation loop mutation localizes symmetrically around the cortex in a manner independent of its binding partner, Par-6, suggesting that aPKC could interact with the cortex by an unknown mechanism.
To investigate how aPKC is able to localize to the cortex independent of Par-6, I used an in vivo structure function analysis of domains within aPKC, accompanied by biochemical approaches. I identified a necessity for the aPKC C1 domain for binding to the neuroblast cortex. This interaction is mediated by negatively charged phospholipids. Neither aPKC interaction, with phospholipids or Par-6, is sufficient to restrict aPKC to the apical cortex. Thus, aPKC polarization utilizes a dual interaction mechanism that takes advantage of both protein-lipid and protein-protein interactions, and proper control of each of these signals is required to prevent neuroblast division defects. One interaction, mediated by the C1, is a general cortical targeting mechanism, whereas the other specifies polarization mediated by Par complex interactions. We conclude that a conformational change induced by these interactions activates aPKC’s catalytic activity, thereby coupling localization and activity.
This dissertation includes unpublished co-authored material.
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Moreau-Gaudry, François. "Apport des bilans catecholaminergiques urinaires dans le diagnostic des neuroblastomes chez l'enfant." Bordeaux 2, 1991. http://www.theses.fr/1991BOR23030.
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