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Ohler, Stephan. "Photoreceptor axon guidance in Drosophila melanogaster." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-144130.
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Goeke, Scott Charles. "The role of lola in axon guidance /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/10639.
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Lerner, Oleg. "Motor axon guidance to the extraocular muscles." Thesis, King's College London (University of London), 2006. https://kclpure.kcl.ac.uk/portal/en/theses/motor-axon-guidance-to-the-extraocular-muscles(4baaa0d2-474a-4b7e-86e5-dd434ac5a9f7).html.
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Zylbersztejn, Kathleen. "Role of vesicular traffic in axon guidance." Paris 7, 2011. http://www.theses.fr/2011PA077146.
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Lors du développement, les molécules de guidage attractives et répulsives, telles que les Sémaphorines (Sema), sont responsables de la formation du réseau neuronal des axones et des dendrites. Les molécules de guidage extracellulaire se lient à des récepteurs qui activent les voies de signalisation intracellulaire et remodèlent le cône de croissance. Le rôle du trafic membranaire dans le guidage axonale est encore largement inconnu. Le trafic membranaire nécessite les protéines SNARE pour la fusion membranaire. La SNARE vésiculaire Synaptobrévine2 (Syb2) est connue pour son rôle dans la libération des neurotransmetteurs dans les neurones matures tandis que TI-VAMP est principalement connue pour son rôle dans la croissance axonale. Leurs rôles potentiels dans le guidage axonale demeurent inconnus. J'ai montré que Syb2 est nécessaire pour la répulsion SemaSA-dépendante, mais pas pour l'attraction SemaSC-dépendante dans des neurones en culture et dans le cerveau murin. Syb2 interagit aussi avec Neuropilinel et PlexinAl, les deux éléments du récepteur à la SemaSA, via son domaine juxta-transmembranaire. Nous concluons que signalisation et la répulsion axonale SemaSA-dépendante nécessitent le trafic vésiculaire Syb2-dépendante. Nous proposons donc un modèle dans lequel la répulsion induite par la SemaSA requiert une endocytose locale accrue et une diminution de l'exocytose. La SemaSA est également impliquée dans le guidage de cellules non neuronales. Certaines de nos observations ont été obtenues dans des cellules non neuronales, suggérant que nos conclusions peuvent s'appliquer généralement à la signalisation de la SemaSADuring development, attractive and repulsive guidance molecules, such as semaphorins (Sema), are responsible for proper wiring of axons and dendrites. Attractive and repulsive external guidance cues bind to receptors which activate intracellular signalling pathways and reshape the growth cone. The role of vesicular traffic in axonal guidance is still largely unknown. Vesicular traffic requires SNAREs proteins for membrane fusion. The exocytic vesicular SNARE Synaptobrevin2 (Syb2) mediates neurotransmitter release in mature neurons while TI-VAMP is mainly known for mediating axon growth. Their potential roles in axon guidance remain elusive. According to a previous model, attraction would rely solely on Syb2-dependent exocytosis while repulsion would exclusively require endocytosis. However, my PhD work has hinted a more complex view on guidance mechanisms. I showed that Syb2 is required for SemaSA-dependent repulsion but not SemaSC-dependent attraction in cultured neurons and in the mouse brain. Syb2 associates with Neuropilinl and PlexinAl, two essential components of the SemaSA receptor, via its juxta-transmembrane domain. We concluded that SemaS A-mediated signalling and axonal repulsion require Syb2-dependent vesicular traffic. We thus propose a model in which SemaSA-induced repulsion is mediated by local increased endocytosis and decreased exocytosis. SemaSA is also involved in non neuronal cell navigation, Some of our observations were obtained in non-neuronal cells further suggesting that our conclusions may more generally apply to SemaSA signaling
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Eberhart, Johann. "EphA4/Ephrin interactions in motor axon guidance /." free to MU campus, to others for purchase, 2002. http://wwwlib.umi.com/cr/mo/fullcit?p3060095.
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Suh, Christopher D. Y. "Identification of axon guidance molecules in C. elegans /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2006. http://uclibs.org/PID/11984.
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Yu, Li. "Dissection of Semaphorin reverse signaling in axon guidance." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96816.
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My PhD thesis describes original study in the guidance of photoreceptor (R-cell) axons in the developing Drosophila visual system. I investigate the role of the transmembrane protein Semaphorin1a (Sema1a) and PlexinA (PlexA) in R-cell axon guidance and dissect the Sema1a reverse signaling pathway. My results indicate that Sema1a functions as a receptor to mediate an attractive response in the Drosophila visual system, and PlexA acts as the upstream regulator of Sema1a.Semaphorins belong to a large family of both secreted and transmembrane proteins known as axon guidance molecules in vertebrates and invertebrates. Drosophila Sema1a is a transmembrane protein. Previous studies have shown that Sema1a functions as the ligand of its receptor PlexA together with Otk inducing a repulsive signaling pathway in the Drosophila neuromuscular system. However, whether it is the case in the Drosophila visual system remains unknown. Our results revealed that sema1a is required in R1-R6 axons for their association and guidance to form a proper topographic termination layer. The function of sema1a in R cells is cell-autonomous. Overexpression of sema1a causes a hyper-fasciculation phenotype in which abnormal thicker bundles are formed in both lamina and medulla. Interestingly, we found that the cytoplasmic domain of Sema1a is required for its function in R-cell axon guidance. All these results suggest that Sema1a functions as an attractive receptor to mediate R-cell interactions during R-cell axon projections, which is totally different with previous studies.Furthermore, I investigate the upstream ligand of Sema1a in our model by testing candidate-gene approach. I found that plexA displays a sema1a-like loss-of-function and gain-of-function phenotype in the Drosophila visual system. In addition, plexA genetically interacts with sema1a. These results indicate that plexA and sema1a function in the same signaling pathway. Interestingly, the cytoplasmic domain of PlexA is dispensable for its function in inducing the hyper-fasciculation phenotype in R-cell axon guidance, suggesting that PlexA functions as a ligand. Epistasis analysis suggests that plexA functions as an upstream regulator of sema1a. Taken all together, we propose that PlexA functions as the ligand of Sema1a in the Sema1a reverse signaling pathway in the Drosophila visual system.Ma thèse de doctorat s'intéresse au rôle des protéines transmembranaires Semaphorin1a (Sema1a) et PlexinA (Plexa) au cours du guidage axonal des photorécepteurs ou cellules R dans le système visuel de la Drosophile. Mes résultats indiquent que Sema1a agit comme un récepteur contrôlant la transmission d'un signal attractif, tandis que PlexA agit en amont de Sema1a. Les sémaphorines sont des protéines soit sécrétées soit transmembranaires qui participent au guidage du cône axonal des neurones, à la régénération axonale, ainsi qu'au développement du tissu nerveux et d'autres tissus. Il a été démontré dans le système neuromusculaire de la Drosophile que Sema1a est une protéine transmembranaire qui, une fois liée a son récepteur PlexA, induit un signal répulsif. Notre analyse de mutants de perte-de-fonction Sema1a révèle que Sema1a est requise pour le guidage des cellules R1-6 et la mise en place de la topographie précise des terminaisons neuronales. La surexpression de Sema1a cause une hyper-fasciculation qui se traduit par la formation de faisceaux neuronaux anormalement épais dans la lamina et la medulla. De plus, nous avons trouvé que la portion cytoplasmique de Sema1a est requise pour son rôle dans le guidage des cellules R. Ainsi, mes résultats suggèrent un nouveau rôle pour Sema-1a en tant que récepteur modulant un effet attractif lors de la projection axonale. Qui plus est, par une approche de gènes candidats j'ai étudié les ligands en amont de Sema-1a. Cette analyse m'a permis de montrer que la perte de fonction ainsi que la surexpression de PlexA induisent des phénotypes similaires a ceux observés chez le mutant Sema1a ou lors de la surexpression de Sema-1a. J'ai également démontré que PlexA interagit génétiquement avec Sema-1a. Ces résultats démontrent que PlexA et Sema-1a fonctionnent au sein de la même voie de signalisation. De façon intéressante la queue cytoplasmique de PlexA est dispensable pour la formation des fascicules neuronaux suggérant que PlexA fonctionne comme un ligand. Finalement des études épistatiques suggèrent que PlexA est en amont de Sema-1a. En conclusion, nous proposons que dans le système visuel de la Drosophile, PlexA soit le ligand de Sema-1a dans une voie de signalisation Sema-1a inversée.
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Tayler, Timothy D. 1972. "Compartmentalization and axon guidance in the Drosophila brain." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/28937.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2005.Includes bibliographical references.
The Drosophila brain is composed of many morphologically and functionally distinct processing centers and brain morphogenesis depends on the creation and maintenance of distinct boundaries between adjacent regions to prevent cells from mixing. In the Drosophila visual system, I have found that Slit and Roundabout (Robo) proteins function to prevent cells from adjacent compartments from mixing. I have defined a boundary between two distinct compartments, the lamina and lobula, and find that the secreted ligand Slit is present in the lamina, while the Robo receptors (Robo, Robo2 and Robo3) are expressed on lobula neurons. I examined the function of theses proteins by identifying a tissue-specific allele of slit and creating transgenic RNAi flies that inhibit the expression of the Robo proteins. Loss of Slit or all three Robo proteins in the visual system results in the invasion of lobula neurons into the lamina. Mixing of cells at the lamina/lobula boundary results in glial cell mispositioning and aberrant photoreceptor axon targeting. Thus, Slit and Robo proteins are required to restrict movement of cells across the lamina/lobula boundary. Additionally, I have characterized Ptpmeg, a highly conserved protein tyrosine phosphatase (PTP). In addition to the C-terminus PTP domain, Ptpmeg contains a central PDZ domain and an N-terminus FERM domain. The in vivo role of this family of proteins is unknown. To explore the function of Ptpmeg in flies, mutants were generated by targeted gene disruption. Examination of the adult nervous system of Ptpmeg mutants reveals a defect in the mushroom bodies (MB), brain structures required for olfactory learning and memory. In mutant animals, the MB lobes are disorganized and fail to elaborate their characteristic structure. I find
(cont.) that Ptpmeg is expressed on MB axons and targeted knockdown of Ptpmeg in the MB results in similar defects as seen in homozygous mutants. Thus, the MB neurons appear to require Ptpmeg for proper formation.
by Timothy D. Tayler.
Ph.D.
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Brown, Samantha. "The mechanisms controlling embryonic axon growth and guidance." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=238413.
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My thesis investigated the mechanisms important for the development of the mammalian optic pathway and whether Primodos, a hormonal pregnancy test drug used between 1958 and 1978, has the potential to cause birth defects. I found that DSCAM (Down's syndrome cell adhesion molecule) is required for the fasciculation and growth of RGC axons. In mice carrying spontaneous mutations in DSCAM (Dscamdel17) normal axon pathfinding occurs. However, growth of axons from the optic chiasm towards their targets is impaired and axon organisation in the optic chiasm and tracts, and RGC growth cone morphologies, are also altered. Conversely, DSCAM gain-of-function resulted in exuberant growth into the dorsal thalamus. In vitro, DSCAM promotes RGC axon growth and fasciculation independently of cell contact. Along with previous work in the lab, my findings identified DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons. Spondins and their LRP binding partners are expressed in both the retina and around the developing optic pathway, consistent with a role in regulating growth of RGC axons towards visual targets. In vitro retinal explant cultures exposed to cells transfected with F-spondin, or its TSR domains, did not however provide evidence of axon growth modulation via F-spondin. I used Zebrafish embryos, a human cell-line and mouse retinal explants to investigate the actions of the components of Primodos upon embryonic axon growth, intersomitic vessel development and changes to cell number, proliferation and cell death. NA/EE-mixture exposure caused rapid morphological damage in Zebrafish embryos, affecting multiple organ systems and affecting physical movement. The NA/EE-mixture also affects nerve outgrowth and blood vessel patterning directly and accumulates in the III developing embryo for at least 24 hours. These data demonstrate that Norethisterone acetate and Ethinyl estradiol are potentially teratogenic, depending on dose applied and embryonic stage of development.
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Sun, Qi Zinn Kai George. "Molecular genetics of axon guidance in Drosophila melanogaster /." Diss., Pasadena, Calif. : California Institute of Technology, 2000. http://resolver.caltech.edu/CaltechETD:etd-03242005-130557.
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Roig, Puiggros Sergi. "Molecular mechanisms orchestrating commissural axon guidance Floor-plate-derived netrin-1 is dispensable for commissural axon guidance Synergistic Activity of Floor-Plateand Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS335.
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Les neurones commissuraux assurent la coordination des informations motrices et somatosensorielles entre les deux moitiés du système nerveux central. Dans la partie caudale du SNC, les axones commissuraux migrent d'abord vers la ligne médiane ventrale, la plaque du plancher, pour la traverser et puis atteindre leur cible finale. Les mécanismes cellulaires et moléculaires qui contrôlent le croisement de la ligne médiane ont fait l'objet d'Etudes approfondies. Ramón y Cajal, dans sa théorie neurotrophique, a suggéré que les cellules de la plaque de plancher pourraient libérer des facteurs diffusibles qui attirent les axones commissuraux vers la ligne médiane ventrale. La nétrine-1, une protéine découverte il y a plus de deux décennies, est une protéine secrétée exprimée à la fois par les cellules de la plaque de plancher et les progéniteurs de la zone ventriculaire et possède une activité chimioattractive à longue distance in vitro. Aujourd'hui, la nétrine-1 est largement acceptée comme l'exemple parfait de la chimioattraction à longue distance. Cependant, nos résultats remettent en question ce modèle, proposant un mécanisme d'action à courte portée de nétrine-1 pendant le guidage des axones commissuraux. En effet, nous avons déterminé que la nÉtrine-1 dérivée de la plaque du plancher n'est pas nécessaire pour le guidage des axones commissuraux. C’est la nétrine-1 dérivée de la zone ventriculaire qui est nécessaire et suffisante pour induire la migration dorso-ventrale des axones commissuraux du cerveau postérieur et leur croisement de la ligne médiane. Nous avons Également confirmé que les progéniteurs de la zone ventriculaire sont la principale source de Netrin-1 pour la migration ventrale des neurones précérébelleux. De plus, nous observons qu'en l'absence de nétrine-1 dérivée de la zone ventriculaire, les axones commissuraux et les neurones précérébelleux envahissent plusieurs nerfs crâniens. Il s’agit d'un procès autonome et dépendant de Dcc. A différence du tronc cérébral, dans la moelle épinière, les deux sources de nétrine-1 agissent en synergie pour assurer le guidage des axones commissuraux et le croisement des lignes médianes. Les neurones commissuraux sont une population diverse distribuée tout au long du système nerveux. Pour analyser la diversité moléculaire des neurones commissuraux du cerveau postérieur et de la moelle épinière, nous avons utilisé des approches combinant la génétique de la souris et la transcriptomique. Nous travaillons actuellement sur de nouveaux facteurs de transcription qui pourraient jouer un rôle dans le développement des neurones commissuraux du tronc et de la moelle épinièreCommissural neurons ensure the coordination of motor and somatosensory information between halves of the central nervous system. In the caudal part of the CNS, commissural axons, first grow toward the ventral midline, the floor plate, to cross it and reach their final target. The cellular and molecular mechanisms controlling midline crossing have been extensively studied. Ram—n y Cajal, in his neurotropic theory, suggested that floor plate cells could release diffusible factors chemo-attracting commissural axons to the ventral midline. Netrin-1, a protein discovered more than 2 decades ago, is a secreted protein expressed both by floor plate cells and ventricular zone progenitors and with long-range chemoattractive activity in vitro. Today, Netrin-1 is widely accepted as the textbook example of long-range chemoattractive guidance cue. However, our results, challenge this model by proposing a short-range mechanism of action for Netrin-1 during commissural axon guidance. Indeed, we determined that floor plate-derived netrin-1 is dispensable for commissural axon guidance. Instead, ventricular zone-derived netrin-1 is necessary and sufficient to promote the dorso-ventral extension of hindbrain commissural axons and midline crossing. We also confirmed that ventricular zone progenitors are the main Netrin-1 source for ventrally migrating precerebellar neurons. In addition, we observe that in absence of ventricular zone-derived netrin-1, commissural axons and precerebellar neurons cell bodies invade several cranial nerves. This appears to be a cell- autonomous and Dcc-dependent process. This mechanism is not conserved in the spinal cord, where both netrin-1 sources act synergistically to ensure commissural axon guidance and midline crossing. Commissural neurons are diverse and found throughout the nervous system. To analyse the molecular diversity of hindbrain and spinal cord commissural neurons, we used approaches combining mouse genetics and transcriptomics. We are currently working on some novel transcription factors that might play a role in the development of hindbrain and spinal cord commissural neurons
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Down, Matthew Paul. "Universal quantitative method for studying axon guidance and its application to Slit-dependent axon guidance at the developing mouse optic chiasm." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/5840.
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Healthy pre-natal development of the mammalian visual system requires that retinal ganglion cell (RGC) axons navigate a precise path to their targets in the thalamus and superior colliculus by making a precise series of turns determined by the complex interactions between growth cone and extracellular environment. One important choice point for RGC axons is the crossing of the midline at the optic chiasm, where ipsilateral/ contralateral sorting takes place. In this thesis a novel image analysis method using steerable filters for quantifying the gross orientation and turning of axons from a static image (such as from DiI filled axons) is presented. This method was applied to understanding Slit dependent axon guidance at the mouse optic chiasm. It was possible to quantify the differences at the chiasm between the wildtype and various classes of mutants involving heterzygous or homozygous knockout of the Slit1 and the Slit2 genes. Assessment was in terms of the spatial distributions in axon density and axon orientation as derived from DiI labeled RGCs originating from one eye. The animals were assessed at embryonic day 13.5. To my knowledge this is the first quantification of its kind in the field of axon guidance. It was found that there were strong statistical differences from wildtype in both the Slit1-/-;Slit2-/- and Slit1+/+;Slit2-/- knockouts in terms of both axon density and axon orientation across large extents of the chiasm. In both these knockouts it was found that the changes in axon density were localised to the anterior region of the chiasm, but the changes in axon orientation were spread across almost the entire extent of the chiasm. No other combination of the Slit1 and Slit2 knockouts for which embryos could be generated showed significant differences from wildtype in terms of spatial changes in axon density or axon orientation. No embryos were generated for the Slit1+/-;Slit2-/- combination. No changes in the spatial distribution of axon density or axon orientation were found between the Slit1-/-;Slit2-/- and Slit1+/+;Slit2-/- knockouts, suggesting that in terms of these two quantities, the two phenotypes are indistinguishable. This evidence suggests that the role of Slit2 is more important than the role of Slit1 at the optic chiasm in terms iii of axon guidance. In addition, the gradients of mRNA expression of Slit1 and Slit2 were quantified using in situ hybridisation, and these data were used to compare the mRNA gradients with the orientation and turning of axons in both the wildtype and Slit1/Slit2 knockout chiasms. Although this provided a powerful visualisation tool, no simple mathematical relationship was found between the mRNA gradient of Slit1 or Slit2 and the orientation or turning of axons at the optic chiasm. These approaches now provide an important suite of methods for spatial analysis of axon tracts and molecular gradients in axon guidance.
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Colavita, Antonio. "Axon guidance along the dorsoventral axis of Caenorhabditis elegans." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ35127.pdf.
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Leung, Louis. "The role of NF-protocadherin in retinal axon guidance." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608776.
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Regan, Aoife Grainne. "A role for semaphorins during axon guidance in Xenopus." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620552.
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Cheng, Ling. "MOLECULAR MECHANISM OF L1CAM FUNCTION: AXON GROWTH AND GUIDANCE." Connect to online version, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1081281361.
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Yeomans, Heather Jane. "Investigations into the functions of immunoglobulin like cell adhesion molecules during vertebrate neural development." Thesis, University of Sheffield, 2001. http://etheses.whiterose.ac.uk/5986/.
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During neural development, each neuron sends an axon out from its cell body. Extending axons are guided by interactions between environmental factors and axonal receptors for these factors. It has been suggested that certain proteins of the immunoglobulin-like superfamily are among the molecules involved in axon guidance. In particular, TAG-1, Ll and NrCAM have previously been implicated in the guidance of dorsal spinal commissural axons at the ventral midline region known as the floor plate. To establish whether these molecules have such roles in mice, the dorsal spinal axons of TAG-1, L1 or NrCAM mutant mouse embryos were traced. There were no significant differences between the results from mutant embryos and their wild type counterparts. This indicated that these three proteins are individually not essential for the normal development of mouse dorsal spinal projections. However, results from TAG-MLI double mutant embryos suggested that TAG- I and LI might affect the ability of commissural axons to extend out of the floor plate. Analysis of ephrin B3 mutant embryos indicated that ephrin B3 might also be important for floor plate exit. As the TAG-1 null mutation includes a lacZ construct, this reporter gene was used to further investigate the roles of TAG-1. Its expression was used to determine distribution of TAG-1 gene activity in the developing mouse nervous system. As the pattern of reporter expression was found to be comparable with that of TAG-1 protein, the TAG-1 null allele was used as a marker for TAG-1-expressing cells in mutant embryos. Most of the structures that normally express TAG-1 seemed to be unaffected by an absence of the protein. However, the hypoglossal nerve was significantly less likely to extend towards the tongue in TAG-1 null homozygous embryos than in heterozygotes. This suggested that TAG-1 might be important for the guidance of hypoglossal axons.
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Vaikakkara, Chithran Aarya. "Axon guidance genes are essential in the adult nervous system." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57654.
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Axon guidance cues are extracellular signals that direct the growth and steering of neuronal growth cones. Both attractive and repulsive cues are required to guide developing axons to their targets. Nonetheless, after axons have reached their targets and established functional circuits, many neurons continue to express these developmental cues. The expression of these genes in the adult indicates that there are likely additional roles for guidance cues beyond the initial phase of neuronal process outgrowth, growth cone navigation, and target innervation. The central goal of my work is to determine the functions of these cues in the mature nervous system. I hypothesize that axon guidance genes expressed in the adult nervous system have functional roles in the maintenance of neural circuits. Work in the past few decades has led to the discovery of numerous axon guidance genes and identified their functions during development. This study is the first to perform an RNA-mediated interference (RNAi) screen for axon guidance genes that have functional roles in the mature nervous system. Axon guidance genes expressed in the adult Drosophila melanogaster nervous system were identified using bio-informatics tools. In Drosophila, more than 96% of embryonic cues continue to be expressed in the adult. The axon guidance genes were knocked down in adult neurons using RNAi via spatial and temporal control of GAL4-UAS system. I have identified 15 axon guidance genes that are essential for survival and normal behavior (climbing, mobility, activity/rest cycle) in adult Drosophila. The results suggests that axon guidance genes are functional in the adult nervous system and may be involved in the maintenance of neural circuits underlying these phenotypes. Further studies on circuit morphology are required to understand better how axon guidance genes contribute to the maintenance of neuronal structure in adult brains.Medicine, Faculty of
Graduate
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Mindorff, Elizabeth. "NF-kappaB signaling and photoreceptor axon guidance in Drosophila melanogaster." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84061.
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During development of the visual system of Drosophila melanogaster , growth cones at the tips of advancing photoreceptor axons respond to instructive cues in the environment and are guided toward appropriate synaptic partners within the optic lobe of the brain. Research has focused on the identification of these molecular cues, their receptors and the signaling processes that mediate their function. This thesis describes the Drosophila line GSd447, which possesses a P element that can support GAL4-mediated transcriptional activation of a gene near the site of insertion. GAL4-driven misexpression of GSd447 in the eye disc causes the R1-R6 photoreceptor axons to be mistargeted. The mistargeted R1-R6 axons fail to terminate in the lamina, and project to a deeper layer in the medulla of the optic lobe. To identify the gene(s) causing these axon targeting defects, two different approaches were used; a candidate gene analysis using UAS-transgenes, and a chemical mutagenesis screen to suppress the mistargeting defects caused by GSd447. Both approaches strongly suggested the NF-kappaB transcription factor, Dorsal, was responsible for the axon targeting defects. In addition, a mutation of cactus, which encodes the inhibitor of Dorsal, was found to genetically interact with GSd447 misexpression to enhance the observed axon targeting defects. Both dorsal and cactus are expressed in photoreceptor cell bodies. Studies of dorsal mutants revealed moderate axon targeting defects using the dorsal alleles identified in the suppression screen. No defects have been found to date in cactus mutants, but severe loss-of-function cactus alleles have not yet been tested. Together, these results and recent studies by others provide evidence for an important role for components of the NF-kappaB signaling pathway in the development of the nervous system in both vertebrates and invertebrates.
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Chilton, John K. "The role of receptor protein tyrosine phosphatases in axon guidance." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365814.
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Peace, Andrew G. "Investigation of the cAMP pathway in axon growth and guidance." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=166172.
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Our investigation suggests that Epac, and not the canonical PKA, is the main effector involved in cAMP-mediated axon growth and guidance, and that the MAPK regulator, B-Raf, can be differentially regulated by both Epac and PKA. Direct activation of Epac induces activation of B-Raf, whereas activation of PKA results in inhibition. Moreover, in embryonic neurons, Epac-B-Raf signalling was found to be activated by the cAMP-dependent guidance molecule Netrin-1 (attractive to developing axons) and by cAMP activity at all levels tested, whereas in adult neurons, PKA signalling was activated by Netrin-1 (repulsive to adult neurons) and low levels of cAMP activity. When cAMP was substantially elevated in adult neurons, Epac-B-Raf signalling was induced, and the response of adult axons to Netrin-1 was switched from repulsion to attraction, indicating B-Raf activity is consistent with chemoattractive axon turning. Furthermore, B-Raf activity was found to localise towards the leading edge of a turning growth cone when visualised with fluorescent microscopy. Neurons lacking B-Raf protein were unable to respond to cAMP-dependent guidance cues and postnatal neurons no longer responded to artificial cAMP elevation, which usually induces an increase in axon outgrowth. Calcium influx into growth cones usually induced by axon guidance cues and cAMP activators, were also attenuated in neurons lacking B-Raf. These data suggest B-Raf is a vital effector for cAMP-mediated axon growth and guidance.
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Hayward, Neil Martin. "Identification and characterisation of axon guidance genes in Drosophila melanogaster." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603902.
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From a collection of lines in which a GAL4 enhancer trap vector is randomly inserted in the genome, five lines were selected based on the restricted expression of GAL4 in the pioneer neurons. Three genes flanking the insertion were successfully cloned by plasmid rescue, and remarkably all are involved in signalling pathways: (i) foraging is a cGMP-dependent protein kinase, with an established role regulating larval behaviour. However, using antibodies made in this study, foraging is not detectable in pioneer neurons, and gain- and loss-of-function experiments show no defects in axon guidance. Given that foraging regulates axonal conductance in larval neurons, it may yet have an embryonic role in pioneer neurons, but at a low expression level. (ii) FKBP12 is a cytoplasmic suppressor of TGF-β signalling. I have shown it to be expressed in neurons where it is localised to axons, and is thus ideally placed for a guidance molecule. I have shown that a potential ligand for this pathway, dpp, is expressed in longitudinal glia, and ectopic expression of dpp can attract axons. (iii) Dfer is a cytoplasmic tyrosine kinase, which I have shown to be expressed in pioneers neurons (dMP2 and MP1). By eliminating Dfer function (using RNAi and a deficiency), I have shown the gene plays a role in guiding axons in the CNS, to prevent longitudinal axons from crossing the midline. Dfer also acts in motor neurons at choice points in the periphery. Continuing analyses of Dfer function should provide an insight into the cytoplasmic processes involved in receiving and interpreting inter-cellular axon guidance signals.
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Yoon, Byung Chul. "Elucidating molecular mechanisms of axon guidance using unbiased proteomic approaches." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609144.
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Wyatt, Cameron. "Optic axon guidance during development and regeneration in the zebrafish." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5947.
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Directed regeneration of axons in the CNS has potential for the treatment of CNS disorders and injuries. In contrast to mammals, following optic nerve lesion zebrafish regenerate axons that navigate to their correct targets and form new synapses leading to functional recovery. Correct pathfinding is thought to rely on a range of molecular cues in the CNS which the growing axon expresses receptors for. However, the specific guidance cues are not well elucidated. It is likely that a proportion of them will be the same as during development, while some may be specific to regeneration. Alternatively, axons may simply retrace former trajectories guided by the molecular environment or mechanical constraints of degenerating tracts, as demonstrated in the mammalian PNS. To elucidate this, we investigated regeneration in the astray/robo2 knockout mutant which exhibits misprojection of optic axons during development leading to the establishment of ectopic tracts. We show that degenerating tracts do not provide a strong guidance cue for regenerating axons in the CNS as ectopic tracts in the astray mutant are not repopulated following lesion despite presenting a similar environment to entopic degenerating tracts. We also find that as astray mutant (knockout) and robo2 morphant (transient knockdown) projection and termination errors persist in the adult, it is clear that there is not an efficient correction mechanism for large-scale pathfinding errors of optic axons during development. In addition, we find a reduced importance of the axon guidance receptor Robo2 and its repellent ligand Slit2 for pathfinding during regeneration as specific developmental pathfinding errors of optic axons in astray mutants are corrected during adult optic nerve regeneration and global overexpression of Slit2 elicits pathfinding defects during development but not regeneration. To address regeneration-associated gene regulation in axotomised retinal ganglion cells, we carried out a microarray analysis. We found that many genes detected as a gradient in the adult retina during regeneration are not differentially expressed in the embryonic eye, despite having distinct expression patterns in other embryonic tissues. Of the genes which exhibit strong differential expression in the retina of both regenerating adults and developing embryos, foxI1 is one of the most interesting candidates as other fox genes have been implicated in axon guidance and due to its highly restricted retinal expression pattern. Surprisingly, further investigation has revealed that foxI1 knockout mutant embryos have retinotectal projections which appear normal in terms of axon pathfinding and mapping. Another family of genes indicated by the array, which are cytosolic phosphoproteins known to be involved in the signal transduction cascade of multiple inhibitory guidance cues during axon growth, are the crmps. Knocking down crmp2 with morpholinos during development resulted in a sparser innervation of the tectum with individual axons which trend towards having less complex arbors with shorter branches and reduced overall axon length. As a whole this work adds to our current knowledge of optic axon guidance during development and regeneration and the relative importance and effect of selected potential guidance cues, which may help toward informing future mammalian CNS regeneration research.
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Yang, Tao. "The role of miRNAs in Slit-mediated commissural axon guidance." University of Toledo / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo154455366176285.
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Flanagan, John James. "Binding specificities of the Dscam family of axon guidance receptors." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1320942751&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Farmer, William Todd. "The role of the floor plate in longitudinal axon guidance." abstract and full text PDF (free order & download UNR users only), 2008. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3316381.
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Song, Hongjun. "Cyclic nucleotide-dependent modulation of axon guidance by diffusible factors /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9835290.
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Parra, Liseth M. "Molecular mechanisms of axon guidance in the developing spinal cord." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3372315.
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Thesis (Ph. D.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed Oct. 6, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 118-124).
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Connor, Robin M. "Mechanisms of axon growth and guidance in the vertebrate nervous system /." [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17183.pdf.
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Tomasi, Tatiana. "The transmembrane protein golden goal regulates retinal axon guidance in Drosophila." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-120022.
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Stoney, Patrick Niall. "The roles of Pax6 in neural precursor migration and axon guidance." Thesis, University of Aberdeen, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=92509.
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The ability of migrating neurons and growth cones to navigate through their environment is crucial for the correct development of the brain. Cells and growth cones may be guided by electrical, chemical or topographical cues in their environment. Pax6 is a transcription factor vital for brain development. Pax6-/- mutant mice die perinatally with defects in neuronal proliferation and differentiation, cortical cell migration and axon guidance, yet it is not clear which guidance cues Pax6-/- mutant neurons fail to interpret. Dissociated cultured cells were used to study the cell-autonomous effects of Pax6 mutation on guidance of growth cones and migrating neural precursors by environmental cues. Neurites from mouse embryonic cortical neurons aligned perpendicular to 1 μm-wide, 130 nm-deep substratum grooves. Pax6-/- mutation abolished contact-mediated neurite guidance by these grooves. Laminin induced a switch from perpendicular to parallel alignment to grooves, via a β1 integrin-independent mechanism. Blocking cAMP signalling abolished perpendicular alignment to polylysine-coated grooves, but enhanced parallel alignment to laminin-coated grooves. Pax6 null mutation or overexpression also caused specific defects in contact-guided migration by cortical cells. An electric field applied to E16.5 cortical neurons increased the frequency of extension of neurites aligned perpendicular to the field axis. Pax6-/- mutant cells responded to an electric field with reduced anodal extension, but no significant increase in perpendicular neurite extension. Electrical cues were prioritised over topographical cues when presented in combination. Taken together, data suggest that Pax6 mutant cortical cells do not completely lack the ability to detect extracellular guidance cues, but they respond differently to wild-type cells. In combination with other defects identified in the cortex, this may contribute to the cell migration and axon guidance phenotypes in the brain of the Pax6-/- embryo. This study also identified novel Pax6 expression in the trigeminal ganglion, where it may regulate axon guidance and neurogenesis.
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Shah, Sheetal Mansukhlal. "Genetic and molecular studies of segmentation and axon guidance in Drosophila." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312177.
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Leung, Kin-Mei. "The role of local β-actin translation in retinal axon guidance." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614324.
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Dinglasan, Lu Anne Velayo. "The role of matrix metalloproteinases in axon guidance and neurite outgrowth." [New Haven, Conn. : s.n.], 2008. http://ymtdl.med.yale.edu/theses/available/etd-12022008-104438/.
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Göhrig, Andreas. "The role of the axon guidance molecule Slit2 in pancreatic cancer." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://dx.doi.org/10.18452/17202.
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Lokale Invasion und Ausbreitung von Tumorzellen entlang von Nerven und Gefäßen limitieren den Erfolg kurativer Therapien von Patienten mit Pankreaskarzinom (PDAC). Der axon guidance Faktor Slit2 und seine Robo-Rezeptoren steuern die Navigation von Nerven und Gefäßen sowie die Motilität von Epithelzellen. Sie stellen somit attraktive Regulatoren der klinisch bedeutsamen Ausbreitungswege des PDAC dar. Zielsetzung der vorgelegten Arbeit war die Charakterisierung der Expression von Slit2 im PDAC und seiner Funktion für Tumorwachstum und -ausbreitung. Quantitative Analysen belegten eine deutliche Reduktion der Slit2 mRNA Expression in humanen PDAC Proben im Vergleich zu gesundem Gewebe. Zudem korrelierten Slit2 mRNA-Werte unterhalb des Medians mit einer höheren Inzidenz lymphatischer Metastasierung und einem gesteigerten Prozentsatz befallener Lymphknoten. Die Slit2-Rezeptoren Robo1 und 4 wiesen hingegen vergleichbare Immunreaktivität im Tumor und gesundem Gewebe auf, wobei eine differentielle Lokalisation in Epithelien, Nerven und Gefäßen zu beobachten war. Die Re-Expression von Slit2 in Slit2-defizienten Zelllinien führte zu einer Hemmung der gerichteten Migration und Invasion. Der Robo1-Rezeptor knockdown hingegen stimulierte die Motilität von Tumorzellen mit endogener Slit2 Expression. Slit2-konditioniertes Medium aus Tumorzellen hemmte die Lamellipodienbildung und die Migration von Endothelzellen. In orthotopen humanen Xenograft-Modellen und einem murinen, syngenen Tumormodell reduzierte die Re-Expression von Slit2 in PDAC Zellen Tumorwachstum, Invasion, Metastasierung und Angiogenese. Zudem verminderte die Induktion von Slit2 in PDAC Zellen deren gerichtete Migration entlang aussprießender Neuriten in einem ex vivo Model. Die vorliegenden Daten weisen Slit2 die Funktion eines Tumorsuppressors im duktalen Pankreaskarzinom zu. Ein Verlust der Slit2-Robo Aktivität könnte somit Metastasierung und neuronale Invasion fördern und einen aggressiveren Phänotyp begünstigen.Early dissemination of pancreatic ductal adenocarcinoma (PDAC) via vascular routes and neural invasion limits curative therapy, suggesting a central role for the interaction of tumor cells with blood vessels and nerves in the tumor stroma. Slit2 and its Robo receptors constitute a system of guidance cues that function in axon guidance, angiogenesis and epithelial morphogenesis, respectively. Here, we studied the expression of Slit2 in PDAC and its function for tumor growth and dissemination. Slit2 mRNA expression was reduced in specimens of human PDAC as compared to non-transformed pancreas and low Slit2 mRNA expression correlated with a higher incidence and a higher extent of lymphatic metastasis. In contrast, the Slit2 receptors Robo1 and Robo4 were uniformly present in clinical samples of PDAC and healthy pancreas and displayed differential localization on epithelial tumor cells, nerves and tumor vasculature. Stable or inducible re-expression of Slit2 in Slit2-deficient PDAC cell lines inhibited directed migration and invasion. Conversely, Robo1-knockdown stimulated the motility of PDAC cells with endogenous Slit2 expression. Tumor cell derived Slit2, furthermore, suppressed lamellipodia formation and migration of primary endothelial cells. In vivo studies in orthotopic human xenograft and mouse syngeneic pancreatic cancer models revealed that re-expression of Slit2 in PDAC cells inhibited tumor growth, invasion, metastasis and angiogenesis. In addition, induction of Slit2 in PDAC cells impaired the unidirectional migration along outgrowing neurites in ex vivo co-cultures of tumor cells and dorsal root ganglia. These data provide evidence for a functional role of Slit2 as a tumor suppressor in human PDAC. A loss of Slit2-Robo activity as observed in human PDAC samples, might consequently promote metastasis and neural invasion and favors a more aggressive phenotype.
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Dinvaut, Sarah. "Champs électriques : un potentiel système de codage des informations spatiales dans l'embryon." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1089.
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La navigation des axones sur de longues distances est jalonnée de zones de choix, entraînant des changements de direction pour suivre des trajectoires hautement stéréotypées. Dans ce modèle de guidage séquentiel, chaque étape est vue comme essentielle à la suivante. De façon intrigante, quelques exemples suggèrent que le suivi strict de la trajectoire puisse être dispensable pour que les axones atteignent leur destination finale. Nous nous sommes intéressés à cette capacité trajectoire indépendante des axones à localiser leur cible. Pour ce faire, nous avons utilisé deux populations neuronales de la moelle épinière ayant des cibles diamétralement opposées dans l'organisme : les interneurones dorsaux, qui projettent dans le système nerveux central, et les motoneurones ventraux, qui ciblent les muscles en périphérie. Après avoir été déplacés chirurgicalement dans des embryons de poulet, ces deux populations de neurones envoient des axones vers leurs territoires cibles qu'ils atteignent par des trajectoires inédites. Ces observations suggèrent l'existence d'un système de guidage global délivrant aux axones des informations spatiales à large échelle. Outre les signaux moléculaires de guidage bien connus, les signaux bioélectriques sont également des candidats intéressants pour remplir cette fonction. Des champs électriques (CE) ont été détectés dans les embryons en développement et sont connus pour être des vecteurs d'information spatiale. Nous avons testé sur des neurones en culture si des CE comparables à ceux mesurés pendant le développement embryonnaire pourraient guider l'élongation des axones moteurs et d'interneurones dorsaux de poulet. Nous avons trouvé que les deux types d'axones s'orientent en direction de la cathode (-) dans un CE. Cependant, ils présentent des sensibilités significativement différentes aux CE, qui pourraient contribuer à des choix de trajectoires différents in vivo. Ensuite, nous avons observé un effet inhibiteur de la Concanavaline A (ConA) sur la réponse des axones aux champs, indiquant un rôle des récepteurs membranaires connus pour lier la ConA. Nous avons donc réalisé un screen pharmacologique sur des pompes et des canaux ioniques qui se lient à la ConA, conduisant à l'identification des pompes Na+/K+ ATPases comme des candidats prometteurs. Des expériences préliminaires d'invalidation des sous-unités de ces pompes suggèrent qu'elles contribuent à la réponse aux CE et à la navigation axonale in vitro et in vivo. Finalement, nos résultats apportent une vision nouvelle des mécanismes assurant la fidélité et la résilience du guidage axonal, et révèlent la contribution méconnue des signaux bioélectriques et des pompes Na+/K+ ATPases au développement neuronalLong distance navigation of axons is marked by choice points, instructing highly stereotyped directional changes of axon trajectories. In this stepwise model, each step is thought to be essential for the next one, but intriguingly, examples suggest that pathway experience can be dispensable for axons to reach their final destination. We investigated pathway-independent ability of axons to locate their target, using two populations of spinal cord neurons having drastically different target location in the organism: the dorsal interneurons, which target the central nervous system and ventral motoneurons, which target muscles. After grafting these neurons at ectopic positions in the chicken embryo, both neuron-types were observed to form axons which, remarkably, oriented towards and reached appropriate targets. This suggests that, in the embryo, an overall guidance information might exist that enables the axons to locate positions over large scales. Beside well-studied chemical cues, bioelectric signals are attractive candidates for this function. Electric Fields (EF) were detected in the embryo and reported to encode spatial information. Thus, using in vitro set-ups, we investigated whether EFs in the range of the ones measured in the embryo could influence the navigation of chick motor and dorsal interneuron axons. We found that both axon subsets orient parallel to EFs. Yet, they significantly exhibited different sensitivities, which could contribute to elicit different trajectory choices in vivo. Next, we found that Concanavalin A (ConA) could block axon response to EF, supporting a role of cell surface receptors known to bind to ConA. Thus, we performed a pharmacological screening on ion channels and pumps that bind ConA and identified Na+/K+ ATPases as promising candidates. Preliminary knock-down experiments targeting Na+/K+ ATPases subunits suggest their contribution to CE response and axon navigation in vitro and in vivo. Collectively, our findings should provide novel insights into the mechanisms ensuring axon guidance fidelity and resilience and reveal unknown contributions of bioelectric signals and Na+/K+ ATPases during neuronal development
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Weng, Yi-Lan. "The Cytoplasmic Adaptor Protein Caskin Participates in LAR-Mediated Motor Axon Guidance." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1301673851.
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Huberman, Andrew David. "Neural activity and axon guidance cue regulation of eye-specific retinogeniculate development /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2004. http://uclibs.org/PID/11984.
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Murray, Andrew J. "The role of cyclic nucleotide signalling pathways in axon growth and guidance." Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487337.
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Finding an effective treatment to repair the damaged mammalian central nervous system (CNS) is one ofthe greatest challenges facing medical science. When damaged, CNS axons are prevented from regenerating by a combination ofenvironmental factors, such as those present on myelin and astrocytes. Neurons themselves though, also have a reduced capacity for regeneration when they mature. Embryonic neurons, for example, are able to regenerate, 'even when transplanted into the mature nervous system, that contains myelin and astrocytic inhibitors, but this ability is lost shortly after birth. One key difference between embryonic and adult neurons that contributes to the lack of regeneration in older cells, is levels ofthe intracellular second messenger, cyclic adenosine monophosphate (cAMP). cAMP levels decline in neurons as the nervous system matures and this correlates with the loss ofregenerative ability with age. Furthermore, artificial cAMP elevation promotes substantial axon regeneration in vivo, and is currently.one ofthe most promising strategies for repairing the damaged nervous systems This study has focussed on targeting cAMP and other signalling molecules to dissect the mechanisms ofaxon growth and guidance and find a more effective target for promoting axon regeneration. Firstly, we tested the strategy pfcAMP elevation in rat dorsal root ganglion (DRG) neurons with an in vitro model ofaxon regeneration. We found that cAMP elevation was effective in promoting regeneration only in early postnatal neurons, adult neuron regeneration was not increased with this treatment. However, targeting of another signalling molecule, cyclic guanosine monophosphate (cGMP) in combination with cAMP was effective at promoting adult axon regeneration. Furthermore,-this could be increased with the concurrent application ofa Nogo receptor blocking peptide, until regeneration comparable to that seen in embryonic neurons was achieved. We feel that this strategy represents an extremely promising approach for examining axon regeneration in vivo. Within cells cA1v1P has two direct targets, protein kinase A (pKA) and the exchange protein activated by cAMP (Epac). Previous studies have indicated that PKA controls cAMP-dependent ~on growth and regeneration. However, Epac has only recently been characterised and a possible role for Epac in axon growth and regeneration has not previously been examined. We have found for the first time that Epac plays a critical role in cAMP-dependent axon growth and regeneration. Selective activation ofEpac mimics cAMP's ability to promote neurite outgrowth and axon regeneration. Furthermore, we have shown that Epac is required for cAMP's ability to promote neurite outgrowth and mediate axon regeneration. This 'provides a target for inducing axon regeneration without altering the cAMP-PKA signalling pathway.. cAMP levels are known to be critical for growth cone responses to extracellular guidance cues. These cues are important during development where they guide an axon to its ultimate target, but some ofthese proteins continue to be expressed in the mature nervous system and contribute to an inhibitory environment after damage. In general high levels ofcAMP in growth cones are thought to mediate attraction to a group of guidance cues, whereas low ~AMP levels initiate repulsion. The exact mechanisms as to how cAMP controls both growth cone attraction and repulsion are not known, although previous studies have indicated that PKA controls both ofthese processes. In this study we have developed a growth cone turning assay that ~llows analysis ofgrowth con~ responses to extracellular gradients in rat DRG neurons. Using this assay along with cAMP analogues specific for Epac orPKA and small interfering RNA (siRNA) we examined growth cone turning to the well characterised guidance molecules, myelin associated glycoprotein (MAG) and netrin-I. We have found that cAMP controls growth cone repulsion and attraction by activating either ofits direct targets. cAMP acts upon Epac to initiate growth cone attraction to MAG or netrin-I, when Epac signalling is perturbed attraction to these molecules is switched to repulsion, and selective Epac activation mimics cAMP's ability to switch repulsion to attraction. Furthermore, growth cones are attracted to a gradient ofan Epac agonist in the same way as they are to cAMP analogues. cAMP acting on PKA controls growth cone repulsion, and repulsion from MAG and netrin-I is abolished when PKA signalling is perturbed, however growth cone attraction is not affected. Additionally, repulsion is observed when growth cones are presented with gradients ofcompounds that selectively activate PKA. In summary, in this work we have examined the signalling pathways that control axon growth and guidance with an aim to provide a future strategy for induCing CNS axon regeneration. For the first time we have shown that Epac plays an important role in cAMP-dependent axon growth, guidance and regeneration andalso that cAMP controls growth cone attraction and repulsion by activating its two direct intracellular targets. We feel that this represents a substantial development in the understanding ofaxon growth mechanisms and hope that it will lead to improved therapies for promoting repair in the damaged CNS.
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Pocock, Roger David John. "T-box gene function during morphogenesis and axon guidance in Caenorhabditis elegans." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400438.
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Lam, Shi-Ying Joyce. "The role of Engrailed in retinal axon guidance and mapping in Xenopus." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608488.
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Hou, Yanli. "Mechanisms of axon guidance and neuronal asymmetry in the nematode Caenorhabditis elegans /." Diss., Digital Dissertations Database. Restricted to UC campuses, 2007. http://uclibs.org/PID/11984.
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Shafer, Jeong Deok Beth. "Planar cell polarity pathway and axon guidance in the developing spinal cord." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3397199.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed March 23, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 95-105).
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Rodino-Klapac, Louise Rose. "Genetic analysis of motor axon pathfinding in Zebrafish." The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1124124345.
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Riley, Kerry Lyn. "Axon guidance cues for the medical longitudinal fascicle in the embryonic chick brain." Thesis, University of Portsmouth, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.478919.
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Erdogan, Burcu. "Therole of microtubule plus-end binding protein TACC3 during axon outgrowth and guidance:." Thesis, Boston College, 2019. http://hdl.handle.net/2345/bc-ir:108581.
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Thesis advisor: Laura Anne LoweryAxon guidance is a critical process in forming the connections between a neuron and its target. Development of a properly functioning nervous system relies heavily on how accurately an axon is guided to the right target. Defects in the guidance machinery may result in neurological disorders. The growth cone that is formed at the tip of a growing axon is responsible for navigating axons to their final targets. The growth cone steers the growing axon towards the appropriate direction by integrating extracellular guidance cues received by membrane-associated receptors at the growth cone periphery. Upon receiving guidance cues, a number of intracellular signal transduction pathways are initiated downstream of the guidance receptors, that can promote or halt growth cone advance. The growth cone generates these responses by remodeling its cytoskeletal components, which are actin network in the periphery and microtubules in the growth cone center. In this thesis, we focus on understanding the role of microtubule dynamics regulation within the growth cone as it makes guidance decisions. Specifically, we examine the role of TACC3 as a microtubule plus-end binding protein during axon outgrowth and guidance. We show that TACC3 localizes at microtubule plus-ends in embryonic Xenopus laevis growth cones and regulates microtubule growth parameters. We also show that TACC3 is important for promoting axon outgrowth in cultured neural tube explants. Furthermore, our data suggests that TACC3 affects axon guidance in vivo and ex vivo. Examination of embryos depleted of TACC3 revealed guidance defects in the spinal cord neurons, while TACC3-overexpressing cultured spinal neurons showed increased resistance to Slit2-induced growth cone collapse. Finally, in an attempt to delineate the mechanism behind TACC3-mediated axon guidance under Slit2, we studied the importance of tyrosine phosphorylation induced by Abelson tyrosine kinase. We find that retaining phosphorylatable tyrosines within the TACC domain is important for its microtubule plus-end tracking behavior and its impact on microtubule dynamics regulation, axon outgrowth and guidance. Together, this thesis contributes new insights to the understanding of the role of TACC3 as a microtubule plus-end binding protein and identifies TACC3 as a potential regulator of axon outgrowth and guidance during Xenopus laevis embryonic development
Thesis (PhD) — Boston College, 2019
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
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McGovern, Vicki L. "Analysis of Axon Guidance in the Embryonic Central Nervous System of Drosophila Melanogaster." The Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1048612222.
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Qu, Chao. "The Coordination of Netrin Signal Transduction via TUBB3 and JNK1 in Axon Guidance." University of Toledo / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1384532180.
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Godfrey, Grayland W. II. "Characterizing the Role of Key Planar Cell Polarity Pathway Components in Axon Guidance." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4841.
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An essential process to the development of the neural network of the nervous system is axon guidance. The noncanonical Wnt/Planar Cell Polarity pathway has been identified as an integral component in controlling the projection of axons during axon guidance. Prickle, ROR1 and ROR2 are PCP related proteins that do not have clearly defined roles in the process. This study aims to use zebrafish CoPA neurons as a model to study the roles of Prickle, ROR1, and ROR2 in axon guidance. Using in situ hybridization, morpholino knockdown, and CRISPR/Cas9 loss of function experiments were able to identify ror1, ror2 and prickle as potential required components in CoPA neuron axon guidance. Elucidating the role of these protein in axon guidance not only will increase our knowledge of the PCP pathway but it will also increase our understanding of the development of the nervous system.