Dissertations / Theses on the topic 'Neuronal signaling'
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1
Sann, Sharon Bree. "Neuronal development roles of calcium signaling /." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3259060.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 21, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Yang, Silei. "Rapid neuronal signaling cascades initiated by corticosterone." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-148762.
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O'Hare, Michael J. "Cell cycle related signaling in neuronal death." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/29368.
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Evidence indicates that neuronal loss in the course of neurodegenerative disease often occurs through programmed death processes. The development of effective therapeutic treatments for such diseases requires detailed knowledge of the intracellular signaling pathways controlling these death processes. Previous work has identified cyclin-dependent kinases, a family of kinases normally involved in the control of cell division, as potential regulators of death in neurons. For instance, a number of events that occur during the G1 to S transition in proliferating cells, such as cyclin D/cdk4 activation and phosphorylation of its target, pRb, have been detected in dying neurons and appear to be essential for death. In the cell cycle, pRb phosphorylation is followed by activation of the transcription factor E2F1. It is not known if E2F1 is also involved in neuronal death. I found that E2F1 expression in neurons induced apoptotic death dependent on Bax but independent of p53. Also, E2F1 mRNA and protein levels increase in neurons induced to die by exposure to low concentrations of K+, and neurons from E2F1 null mice are resistant to this death. These results are consistent with participation of endogenous E2F1 in neuronal death signaling.
Cdk5 is a member of the cyclin-dependent kinase family which does not have a function in the cell cycle. Instead cdk5, together with its binding partners p35 and p39, is involved in a variety of neuronal functions. Cleavage of p35 into a smaller p25 form has been shown to convert cdk5 into a death promoting kinase. However, it is not yet clear under which circumstances cdk5 signals death, and there is also some contrasting evidence suggesting cdk5 is a pro-survival factor. By targeting dominant negative cdk5 expression to either the nuclear or cytoplasmic compartments I show that cdk5 performs a pro-death function within the nucleus but a pro-survival function within the cytoplasm. The nuclear pro-death signal is relevant only when p25 is produced early, as it is following glutamate induced death, and not when it is produced late as a result of caspase activation, as it is following DNA damage.
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Tornieri, Karine. "Signaling Mechanisms Regulating Neuronal Growth Cone Dynamics." Digital Archive @ GSU, 2008. http://digitalarchive.gsu.edu/biology_diss/48.
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During the development of the nervous system, neurons migrate to their final location and extend neurites that navigate long distances in the extracellular environment to reach their synaptic targets. The proper functioning of the nervous system depends on correct connectivity, and mistakes in the wiring of the nervous system lead to brain abnormalities and mental illness. Growth cones are motile structures located at the tip of extending neurites that sense and respond to guidance cues encountered along the path toward their targets. Binding of these cues to receptors located on growth cone filopodia and lamellipodia triggers intracellular signaling pathways that regulate growth cone cytoskeletal dynamics. Although studies on extracellular cues and their effects on neuronal guidance are well documented, less is known about the intracellular signaling mechanisms that regulate growth cone motility. This dissertation focuses on two signaling pathways and describes how they might be involved in determining growth cone morphology during neuronal development. The specific aims of this work address: (1) the role of phosphatidylinositol-3-kinase (PI-3K) and its downstream signaling pathway in regulating growth cone motility, and (2) the effect of nitric oxide (NO) release from a single cell on growth cone morphology of neighboring neurons. This study employs defined neurons from the pond snail, Helisoma trivolvis, to demonstrate that inhibition of PI-3K induces a concomitant increase in filopodial length and a decrease in the rate at which neurites advance. These effects are mediated through the lipid and protein kinase activities of PI-3K, and filopodial elongation is due to an increase in the rate at which filopodia elongate and the time that individual filopodia spend extending. Additionally, this study demonstrates that NO release from a single cell can affect growth cone dynamics on neighboring neurons via soluble guanylyl cyclase (sGC), and that NO has a physiological effect up to a distance of 100 ìm. Overall this study provides new information on cellular mechanisms regulating growth cone motility, and suggests a potential role of PI-3K and NO in neuronal pathfinding in vivo.
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Rogoz, Katarzyna. "Signaling Mechanisms in the Neuronal Networks of Pain and Itch." Doctoral thesis, Uppsala universitet, Genetisk utvecklingsbiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-183255.
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Glutamate is the essential neurotransmitters in pain pathways. The discovery of the vesicular glutamate transporters (VGLUT1-3) has been a fundamental step on the way to describe glutamate-dependent pain pathways. We used the Cre-lox system to construct conditional knockouts with deficient Vglut2 transmission in specific neuronal populations. We generated a Vglut2f/f;Ht-Pa-Cre line to selectively delete Vglut2 from the peripheral nervous system. These Vglut2 deficient mice showed decreased acute nociceptive responses and were less prone to develop an inflammatory state. They did not develop cold allodynia, or heat hyperalgesia and were less hypersensitive to mechanical stimuli in the PSNL chronic pain model. Further analyses of genes with altered expression after nerve injury, revealed candidates for future studies of chronic pain biomarkers. Interestingly, the Vglut2f/f;Ht-Pa-Cre mice developed an elevated itch behavior. To investigate more specific neuronal populations, we analyzed mice lacking Vglut2 in the Nav1.8 population, as inflammatory hyperalgesia, cold pain, and noxious mechanosensation have been shown to depend upon Nav1.8Cre positive sensory neurons. We showed that deleting Vglut2 in Nav1.8Cre positive neurons abolished thermal hyperalgesia in persistent inflammatory models and responses to noxious mechanical stimuli. We also demonstrated that substance P and VGLUT2-dependent glutamatergic transmission are co-required for the development of formalin-induced inflammatory pain and heat hyperalgesia in persistent inflammatory states. Deletion of Vglut2 in a subpopulation of neurons overlapping with the vanilloid receptor (TRPV1) primary afferents in the dorsal root ganglia resulted in a dramatic increase in itch behavior accompanied by a reduced responsiveness to thermal pain. Substance P signaling and VGLUT2-mediated glutamatergic transmission in TRPV1 neurons was co-required for the development of inflammatory pain states. Analyses of an itch phenotype uncovered the pathway within TRPV1 neurons, with VGLUT2 playing a regulatory role and GRPR neurons, which are to plausible converge the itch signal in the spinal cord. These studies confirmed the essential role of VGLUT2-dependent glutamatergic transmission in acute and persistent pain states and identified the roles of specific subpopulations of primary afferent neurons. Additionally, a novel pain and itch transmission pathway in TRPV1/VGLUT2 positive neurons was identified, which could be part of the gate control of pain.
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Cui, Rui. "The role of Ryanodine receptors in neuronal calcium signaling." Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/705.
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Calcium (Ca2+) is a universal second messenger controlling a wide variety of cellular reactions and adaptive responses. All the versatility of a Ca2+ signaling requires that the concentration of Ca2+ ions in the cytoplasm be highly regulated. Generation of Ca2+ mobilizing signals in cells involves regulation by multiple components controlling Ca2+ release from the internal stores, Ca2+ influx across the plasma membrane, elicitation of Ca2+ sensitive processes and finally the removal of Ca2+ from the cells.
Inositol-1, 4, 5-trisphosphate receptors (IP3Rs) and ryandine receptors (RyRs) are the most studied Ca2+ release channels located on the internal stores. Previous studies have shown ryanodine receptors (RyRs) play a key role in the process of Ca2+ signaling participating in the oscillatory patterns of controlling the release of Ca2+ from ER and regulating the influx of Ca2+ by coupling with plasma Ca2+ channels. Although recent progress deciphered the behavior and function of RyRs in regulation of Ca2+ signal, it still remains mysterious in understanding the molecular mechanism of its regulation and its connection with plasma membrane Ca2+ channels in neuronal cells. Here this study aimed to utilized the most cutting-edge RNA interference techniques, along with well-characterized pharmacological regulators of RyRs, to better characterized the role of RyRs is our neuronal cell line model NG115-401L.
Our first main goal of this project was to develop an effective protocol that could selectively knockout or knockdown expression levels of the RyR1 gene in NG115-401L cells. After testing different siRNA primers including their combination with different transfection reagent, the result shows a significant silencing effect to the RyR1 mRNA expression levels. In the second part of this study, we used a group of pharmacological agents with well-known regulatory actions on RyRs to characterize the functional roles of the RyRs expressed in NG115-401L cells. All four agonists which are ryanodine, caffeine, CMC and PCB 95 show their abilities to activate the RyRs, increase [Ca2+]iand induce the influx of Ca2+ via SOC. After transfected NG115-401L cells by siRNA, the Ca2+ release and influx signals were highly diminished suggesting RyR1 gene was successfully knocked down and the successfully knocked down and the Ca2+ mobilization mediated by RyR1 was decreased greatly. Finally in order to study the effects of the regulation of Ca2+ by RyR modulators and RyR gene knockdown on cell growth patterns and cell viability, the NG115-401L cells were exposed to various concentrations of RyR regulators and siRyR1 primer for different time periods. The siRNA transfection showed the least effect on cell growth, as compared with pharmacological agents that modulate RyR function. Considering we achieved high levels of gene knockdown and its low cytotoxity, our result suggests that siRNA silencing for RyRs may become a promising gene therapeutic target in the future.
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Guo, Jing. "Studying the signaling pathways in ROS-induced neuronal cell death /." View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202005%20GUO.
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Suen, Ka-chun, and 孫嘉俊. "Molecular signaling of neuronal apoptosis in beta-amyloid peptide neurotoxicity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31245961.
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Figueroa-Masot, Xavier Andres. "The role of JNK signaling and Bcl-2 in neuronal function : from apoptosis to neuron excitability /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/10647.
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Krjukova, Jelena. "Investigation on Pre- and Postsynaptic Ca2+ Signaling in Neuronal Model Systems." Doctoral thesis, Uppsala universitet, Institutionen för neurovetenskap, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4300.
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Communication between neuronal and non-neuronal is called volume transmission when the released neurotransmitter (NT) acts via diffusion and affects several target cells. Both the neurosecretory and postsynaptic cell responses are linked to [Ca2+]i elevations. In the present thesis the role of pre-and postsynaptic Ca2+ elevations has been investigated in the reconstituted "synapse" model comprised of NGF-differentiated PC12 and HEL cells as well as in SH-SY5Y neuroblastoma cells. In PC12 cells, both 70mM K+ and nicotine triggered NT release, which could be detected as a secondary [Ca2+]i increase in surrounding HEL cells. Both secretagogues shared the same voltage-dependent Ca2+ influx pathway as judged from the pharmacological profile blockers of voltage-gated Ca2+ channels. The coupling of electrical responses to the activation of Ca2+ signaling via muscarinic receptors in SH-SY5Y cells was also studied. These data revealed that depolarization caused a considerable potentiation of the muscarinic Ca2+ response. The potentiated Ca2+ increase was mainly dependent on the enhanced Ca2+ influx and to a lesser extent on [Ca2+]i release from intracellular stores. A phospholipase C (PLC) activator, m-3M3FBS was used to further study the role of G-protein coupled receptor (GPCR)-coupled Ca2+ signaling. However, it was found that m-3M3FBS instead triggered [Ca2+]i elevations independently of PLC activation. In conclusion, the results indicate that the magnitude of NT release from PC12 cells is sufficient to cause a robust activation of neighboring target cells. Postsynaptic muscarinic signaling is amplified due to integration of electrical excitation and GPCR signaling. The PLC activator, m-3M3FBS is not suitable for studies of PLC-mediated signals in intact cells.
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Traynham, Christopher J. "Effects of Neuronal Nitric Oxide Synthase Signaling On Myocyte Contractile Function." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305058816.
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Ramos, Fresnida. "Neuronal insulin signaling and the regulation of mammalian lifespan a dissertation /." San Antonio : UTHSC, 2008. http://proquest.umi.com.libproxy.uthscsa.edu/pqdweb?did=1588771411&sid=2&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Teo, Jia-Ling. "Presenilin-1 and TCF/[beta]-catenin signaling : effects on neuronal differentiation /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/9311.
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Javier, Torrent Míriam. "Role of PS/γ-secretase-mediated signaling during neuronal development and degeneration." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666905.
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Presenilina-1 (PS1), el component catalític de γ-secretasa que regula el processament de múltiples proteïnes transmembrana, es troba mutada en la majoria de casos d’Alzheimer familiar (FAD). Evidències recents indiquen que mutacions en PS1 lligades a FAD redueixen el processament de múltiples proteïnes transmembrana, suggerint un mecanisme de pèrdua de funció. De fet, la inactivació de PS1 durant l’embriogènesi comporta defectes morfològics, mentre que la inactivació genètica d’ambdues PS en el cervell adult causa defectes en memòria dependents d’edat i neurodegeneració. A més, la participació de PS en la proteòlisi de molècules de senyalització implicades en el desenvolupament del sistema nerviós, incloent ErbB4, suggereix que aquestes vies de senyalització podrien contribuir a la neurodegeneració.
En aquesta tesi doctoral hem estudiat el paper del processament dependent de PS1/γ‑secretasa d’EphA3 i de la senyalització Nrg1/ErbB4 en el desenvolupament neuronal i la neurodegeneració. Els nostres resultats mostren que PS1/γ-secretasa és necessària pel creixement axonal en el cervell en desenvolupament. PS1/γ-secretasa regula l’elongació axonal a través de l’escissió d’EphA3 en la tirosina 560 que resulta en la generació d’un fragment ICD. EphA3 ICD regula negativament RhoA, interacciona amb la miosina IIA no-muscular (NMIIA) i incrementa la seva fosforilació (S1943) produint el desmuntatge del filament i el creixement axonal. De manera contrària a la senyalització clàssica ephrin-EphA3, la senyalització d’EphA3 dependent de PS/γ-secretasa és independent de lligand. Aquest resultat suggereix per primer cop papers oposats d’EphA3 inhibint (dependent de lligand) o promovent (processament dependent de PS1/γ-secretasa) el creixement axonal en neurones. En segon lloc, mostrem que PS1/γ-secretasa regula l’expressió de Nrg1 tipus III i el processament de Nrg1 tipus III i ErbB4, i regula negativament la sinaptogènesi a través de Nrg1. En conjunt, els nostres resultats mostren que PS1/γ-secretasa regula el creixement axonal i la sinaptogènesi a través de la regulació de la senyalització d’EphA3 independent de lligand i del processament/senyalització de Nrg1/ErbB4, respectivament. La nostra investigació obre el camí a explorar noves relacions entre el neurodesenvolupament i la neurodegeneració, proporcionant evidències sobre l’existència d’una comunicació entre les vies de senyalització implicades en aquests processos.Presenilin-1 (PS1), the catalytic component of γ-secretase that regulates the processing of multiple transmembrane proteins is mutated in the majority of cases of familial Alzheimer’s disease (FAD). Recent evidence indicates that FAD-linked PS1 mutations reduce the γ-secretase cleavage of several transmembrane proteins, suggesting a loss-of-function mechanism. Indeed, PS1 inactivation during embryogenesis leads to morphological defects, whereas genetic inactivation of both PS in the adult brain causes age-dependent memory impairments and neurodegeneration. Moreover, the participation of PS in the proteolysis of signaling molecules involved in the development of nervous system, including ErbB4, suggest that these signaling pathways could contribute to neurodegeneration. In this doctoral thesis we have studied the role of PS1/γ-secretase-dependent cleavage of EphA3 and Nrg1/ErbB4 signaling in neuronal development and neurodegeneration. Our results show that PS1/γ-secretase is required for axon growth in the developing brain. PS1/γ-secretase mediates axon elongation through the cleavage of EphA3 at Tyr560 resulting in the generation of an ICD fragment. EphA3 ICD regulates negatively RhoA, and interacts with and increases phosphorylation (S1943) of non-muscle myosin IIA (NMIIA) leading to filament disassembly and axon growth. In contrast to the classical ephrin/EphA3 signaling, PS/γ-secretase-dependent EphA3 signaling is independent of ligand. This result suggests for the first time opposite roles of EphA3 on inhibiting (ligand-dependent) and enhancing (PS/γ-secretase-dependent processing) axon growth in neurons. Second, we show that PS/γ-secretase regulates Nrg1 type III expression, mediates the processing of Nrg1 type III and ErbB4 and regulates negatively synaptogenesis through Nrg1. Taken together, our results show that PS1/γ-secretase regulates axon growth and synaptogenesis by regulating ligand-independent EphA3 signalling and Nrg1/ErbB4 processing/signalling, respectively. Our investigation paves the way for exploring new relationships between neurodevelopment and neurodegeneration, providing insights of the existence of a crosstalk among the signaling pathways involved in these processes.
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Roux, Philippe P. "Signaling pathways implicated in p75 neurotrophin receptor-mediated neuronal survival and death." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38267.
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The neurotrophins are growth factors involved in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases, and the p75 neurotrophin receptor (p75NTR). In contrast to the rapid progress made in elucidating the mechanism of action of the Trk receptors, the physiological roles of p75NTR are uncertain, but two general functions have been ascribed to p75NTR. First, p75NTR can positively or negatively modulate Trk receptor signaling, and second, p75NTR can autonomously activate signaling cascades that results in cellular apoptosis. The signaling pathways employed by p75NTR to mediate its effects are unclear, but p75NTR was found to activate the NF-kappaB and JNK pathways, and to interact with several adaptor proteins, such as NRAGE, NADE, NRIF, TRAF proteins, and FAP-1.Nervous system injuries represent interesting models to study p75NTR because several types of injury induce p75NTR expression. In the first part of this thesis, we have used the pilocarpine model of seizure in the rat and found that this type of injury induces neuronal apoptosis and p75NTR expression. Apoptosis was tightly linked with p75NTR expression, suggesting that p75NTR may promote apoptosic cell death after seizure, and consistent with this, we have found that p75NTR can promote JNK activation and apoptosis in vitro. In the second study, we discovered that p75NTR can also facilitate survival under some cellular circumstances. The survival-promoting effect of p75NTR was accompanied with PI3-K-dependent Akt activation, and correlated with a reduction in cytosolic protein tyrosine phosphatase activity, suggesting that p75NTR may regulate a tyrosine phosphatase involved in the regulation of Akt and survival. In the last study, we have found that the related neuroprotective compounds, K252a and CEP 1347, are potent. MLK3 inhibitors, yet they simultaneously activated Akt and ERK, and survival through MLK3-independent mechanisms. These findings suggested that K252a and CEP1347 may act on a novel target responsible for their survival-promoting activities.
Taken together, the data in this thesis adds to our understanding of the physiological functions of p75NTR, and contributes to our knowledge of the cellular machinery that control neuronal cell survival and death.
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Yang, Silei [Verfasser], and Rainer [Akademischer Betreuer] Landgraf. "Rapid neuronal signaling cascades initiated by corticosterone / Silei Yang. Betreuer: Rainer Landgraf." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1027066143/34.
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Wang, Xinnan. "Neuronal and signaling roles of a Drosophila hereditary spastic paraplegia gene SPG6." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612846.
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Shoop, Richard D. "Localization and calcium signaling of neuronal nicotinic acetylcholine receptors on somatic spines /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9975047.
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Muta, Kenjiro. "The role of neuronal mTORC1 signaling in the regulation of physiological processes." Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/1706.
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The mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved serine/threonine kinase regulating diverse cellular functions, including cell growth, protein synthesis and sensing nutrients and energy status. Prior studies have identified the involvement of hypothalamic mTORC1 in the control of energy balance, renal sympathetic activation and blood pressure regulation.
Hypothalamic insulin receptor signaling through the phosphatidylinositol 3-kinase (PI3K) is known to regulate energy homeostasis and sympathetic nerve activity (SNA). We examined the role of hypothalamic mTORC1 in the anorectic and sympathetic effects of central insulin. mTORC1 inhibition by rapamycin or PI3K mutation resulted in blunted regional SNA responses to insulin. Rapamycin also blunted appetite-suppressing and body weight-reducing effects of insulin. Furthermore, biochemical analyses revealed PI3K-dependent activation of mTORC1 pathway by insulin in the arcuate nucleus of hypothalamus (ARC), where insulin initiates its central actions. These results indicate the significant contribution of mTORC1 pathway in the ARC to the central action of insulin on the regulation of energy homeostasis and SNA.
Angiotensin II (Ang II) is a vasoconstrictive and anti-diuretic peptide produced in the renin-angiotensin system (RAS). Local brain RAS plays an important role in the control of blood pressure, electrolyte and fluid balance. Stimulation of Ang type 1 receptor (AT1R) by Ang II in the cardiovascular brain nuclei triggers drinking and pressor responses. Chronic Ang II action in CNS leads to transcriptional neuromodulation, which in turn, contributes to the development and maintenance of hypertension. Intracellular signaling cascades responsible for neuronal Ang II's actions include PI3K and extracellular signal-regulated kinase (ERK) pathways, which are known upstream effectors of mTORC1 in peripheral tissues. We investigated the involvement of mTORC1 signaling in the brain Ang II actions. Ang II was capable of activating mTORC1 in neuronal cell line and mouse brain, however mTORC1 inhibition had no influence on the drinking and pressor responses to Ang II. Moreover, we found an upregulated mTORC1 activity in the SFO of hypertensive transgenic mice with overactive brain RAS (sRA mice). Importantly, mTORC1 inhibition normalized systolic blood pressure in sRA mice. These results support a potential role of mTORC1 in the maintenance of neurogenic hypertension.
Overall, data presented in this thesis provide a better understanding of neuronal mTORC1 function as a key effector component of insulin or Ang II-mediating regulation of physiological and pathophysiological processes.
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Jiang, Xiaosong. "Muscle induces neuronal expression of acetylcholinesterase in neuron-muscle co-culture : transcription regulation mediated by cAMP-dependent signaling /." View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202003%20JIANG.
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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003.Includes bibliographical references (leaves 132-149). Also available in electronic version. Access restricted to campus users.
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Kam, Ka-man. "Expression analysis of Hoxb5 in enteric neurons and generation of Tamoxifen inducible Cre mice for neuronal Hoxb5 signaling perturbation." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290574.
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Miloş, Ruxandra-Iulia. "In vivo analysis of the neuronal calcium signaling in the developing visual cortex." kostenfrei, 2008. http://mediatum2.ub.tum.de/doc/627379/627379.pdf.
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Roof, Steve. "Neuronal Nitric Oxide Synthase Signaling Contributes to the Beneficial Cardiac Effects of Exercise." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354048916.
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Johnson, Christopher M. "Investigating the Slow Axonal Transport of Neurofilaments: A Precursor for Optimal Neuronal Signaling." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1452018547.
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Ng, Yu Pong. "Leukemia inhibitory factor receptor signaling in NGF-induced neuronal differentiation of PC12 cells /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BICH%202004%20NG.
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Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2004.Includes bibliographical references (leaves 134-172). Also available in electronic version. Access restricted to campus users.
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Mejia, Luis Antonio. "Interaction Proteomics of Autism Spectrum Disorder- and Intellectual Disability-Associated Proteins Identifies a Novel Hap1-Tsc1 Signaling Link that Controls Neuronal mTORC1 Signaling and Pyramidal Neuron Morphogenesis." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11190.
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Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders of cognition that remain incompletely understood. Here, using a computation-assisted interaction proteomics approach in neural cells including primary neurons, we isolate high-confidence binding partners of proteins linked to ASD and ID. As part of these studies, we uncover the brain-enriched, coiled-coil domain protein huntingtin-associated protein 1 (Hap1) as a novel functional binding partner of the tuberous sclerosis complex (TSC) protein Tsc1. We validate and map the Hap1-Tsc1 interaction, and find that Hap1 and Tsc1 form a complex endogenously in the brain. Hap1 knockdown in primary hippocampal neurons triggers the specification of supernumerary axons, and in utero knockdown of Hap1 in mice profoundly impairs the positioning of pyramidal neurons in the hippocampus in vivo. Importantly, the Hap1 knockdown-induced phenotypes in primary neurons and in vivo recapitulate the phenotypes induced by Tsc1 knockdown. We also define a mechanism by which Hap1 regulates Tsc1 function. We observed that exogenous Hap1 promotes the abundance of soluble, stable Tsc1 expressed in cells. Hap1 knockdown in neurons reduces Tsc1 abundance and accordingly stimulates the activity of mTORC1, as reflected by phosphorylation of the ribosomal protein S6. Importantly, inhibition of mTORC1 signaling suppresses the Hap1 knockdown-induced axon phenotype in hippocampal neurons. Collectively, these findings define a novel relationship between Hap1 and Tsc1 that regulates neuronal Tsc1 abundance, pyramidal neuron development, and neuronal mTORC1 signaling, with important mechanistic implications for our understanding of neurodevelopmental disorders of cognition.
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Arthur, David Benjamin. "Extracellular nucleotide signaling in neuronal differentiation and survival Multiple roles of the P2Y₂ receptor /." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3205808.
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Thesis (Ph. D.)--University of California, San Diego, 2006.Title from first page of PDF file (viewed April 3, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 139-159).
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Coffill, Cynthia Rose. "The study of signaling pathways controlling neuronal apoptosis inhibitory protein (NAIP) expression and function." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/29345.
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Deletions in the gene for Neuronal Apoptosis Inhibitory Protein ( NAIP) have been suggested to exacerbate the severity of motor neuron loss in patients with Spinal Muscular Atrophy (SMA). NAIP is the founding mammalian member of the inhibitor of apoptosis (IAP) protein family that is characterized by highly conserved amino-terminal motifs called baculovirus IAP repeats (BIR). Previous in vitro and in vivo analyses with an adenovirus expressing NAIP but lacking exons 14 and 17 of the full-length cDNA (NAIPDeltaE14/17) displayed measurable cytoprotection against apoptosic-induced cell death. In the present study, cytoprotective effects were obtained with adeno-NAIPDeltaE14/17 alone in the human neuroblastoma SH-SYSY. Pretreatment of these cells with trophic factors failed to improve the cytoprotection mediated by NAIP. Similarly, the anti-apoptosic effect of NAIP was observed in HeLa cells transiently transfected with constructs expressing full-length NAIP and NAIPDeltaE14/17. To further investigate NAIP's cellular role, human HeLa and rat PC12 stable cell lines were developed by integrating a tetracycline-dependent transcription factor construct that was able to selectively regulate a second DNA construct containing full-length NAIP. Doxorubicin, etoposide and TNFalpha were used to test the cytoprotectiveness of NAIP. Surprisingly, cells overexpressing the full-length NAIP protein did not display increased survival, as determined by a WST-1 metabolism assay, suggesting that long-term exposure to an IAP may result in cellular compensatory mechanism.
In an effort to delineate the signal transduction pathways that modulate the genes encoding marine Naip, the neuroblastoma cell line, neuro-2a was exposed to a number of signaling pathway specific inhibitors and activators. Cyclic AMP analogs, db-cAMP and 8-Br-cAMP both increased the Naip transcript, as did the plant isoflavone, genistein. Serum starvation was also found to increase Naip levels. We show that sodium butyrate (NaB), a broad-spectrum activator of many signaling pathways, increased the Naip mRNA levels of by 3-fold. By focusing on the NaB induction, it appears that Naip can be modulated by more than one signaling pathway as inhibition of JAK2 in the presence of NaB resulted in a significant and additive increase in the Naip transcript. In combination with various kinase inhibitors, the NaB-induced up-regulation was found not be dependent on the ERK, p38 or PKA pathways. A broad based kinase inhibitor, H-7 down-regulated Naip and also attenuated the NaB-induced up-regulation of Naip. Our data suggest that the Naip gene can be induced by NaB through the H-7 sensitive PKC or PKG but not PKA-pathways.
To examine whether or not the third BIR domain of NAIP (NBIR3) inhibits caspase-9, recombinant GST-NBIR3 protein was overexpressed, purified, and successfully used to demonstrate inhibition of this initator caspase. Through binding analyses a Smac-based peptide, which has been shown to be an IAP antagonist, and NBIR3 were shown to interact with a KD of 52 nM and similar to the third BIR domain of XIAP (XBIR3). Interestingly, and in contrast to XBIR3, the processed Smac protein does not appear to interact with NBIR3 as association could not be detected during a pull-down study, suggesting that other interactions between the proteins are important. In a search for unique binding partners for NBIR3, a phage display library was panned for a binding consensus sequence. Following the identification of a number of human proteins containing this sequence, TRABID a candidate protein was chosen for testing. In the TNFalpha, signaling pathway, TRAF6 can interact with both TRABID and TAK1 while NAIP can bind TAK1 but it does not appear that TRABID and NBIR3 directly interact based on pull-down studies.
Overall, through the examination of NAIP induction, signaling pathways that had not previously been associated with the up-regulation of an IAP were identified and characterized. In the exploration of anti-apoptosic activity, the third BIR domain of NAIP was shown to act in a similar mariner to the other IAPs containing three BIR motifs by inhibiting caspase-9 and interacting with a peptide based on the antagonist, Smac. These findings can potentially lead to therapeutic interventions in degenerative diseases with dysregulated apoptosis.
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Krjukova, Jelena. "Investigation on Pre- and Postsynaptic Ca2+ Signaling in Neuronal Model Systems." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4300.
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Garcia, Rodrigo I. S. M. Massachusetts Institute of Technology. "Cell-type specific contributions to Rett Syndrome : neuronal and astrocytic signaling and sensory processing." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/106431.
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Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016.Page 127 blank. Cataloged from PDF version of thesis.
Includes bibliographical references.
Loss of function mutations in the X-linked gene encoding for MeCP2 are the underlying genetic cause for Rett Syndrome (RTT), a devastating neurodevelopmental disorder that primarily affects girls. While the function of this transcriptional regulator remains elusive and complex, recent focus has turned to downstream signaling pathways as putative targets for novel therapeutics. The complexity of MeCP2 function is compounded by the heterogeneity of cell types in the brain, with recent evidence implicating glia cells in RTT pathophysiology. The focus of my thesis has been two-fold: exploring signaling mechanisms downstream of MeCP2 and the potential of IGF-1 as a therapeutic for RTT, and examining functional astrocyte sensory processing in healthy and impaired circuits. I present evidence that IGF-1 levels are reduced in mouse models of RTT and systemic treatment with IGF-1 leads to improvements in lifespan, respiratory patterns, and social behaviors. These effects are accompanied by increased synaptic proteins, activation of signaling pathways, and enhanced excitatory transmission, as well as effects on plasticity in visual cortex circuits. Astrocytes, known to contribute to synapse formation and maintenance, have been implicated alongside neurons as contributors to the RTT phenotype. They express the two most abundant glutamate transporters in the brain responsible for the majority of glutamate clearance from synapses. Indeed, lack of MeCP2 in astrocytes leads to a reduction in signaling pathways and aberrant glutamate transporter expression, with strong implications for synaptic and circuit activity. Efficient processing of visual information requires processing salient features while overcoming the inherent variability in neuronal networks. Natural movies evoke reliable responses from pyramidal neurons in visual cortex and my work reveals that discrete microdomain regions of visual cortex astrocytes also exhibit temporally reliable and spatially correlated responses to natural scenes. I show that glutamate transporters, which influence astrocytic Ca 2 signaling and synaptic transmission, regulate the reliability of astrocyte microdomain responses and thus contribute crucially to visual information processing. Finally, I show that in a RTT mouse model, astrocyte microdomains elicited by visual stimuli are reduced in size, consistent with the reduced synaptic transmission and neuronal responses observed in these mice.
by Rodrigo I. Garcia.
Ph. D. in Neuroscience
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Tang, Lifei. "Effects of Neuronal Nitric Oxide Synthase Signaling on Myocyte Contraction during Beta-Adrenergic Stimulation." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385336408.
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Stepan, Jens [Verfasser], and Angelika [Akademischer Betreuer] Erhardt. "Enhanced endocannabinoid signaling modulates neuronal network dynamics in the hippocampus / Jens Stepan ; Betreuer: Angelika Erhardt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1160875855/34.
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Moore-Dotson, Johnnie M., Jamie J. Beckman, Reece E. Mazade, Mrinalini Hoon, Adam S. Bernstein, Melissa J. Romero-Aleshire, Heddwen L. Brooks, and Erika D. Eggers. "Early Retinal Neuronal Dysfunction in Diabetic Mice: Reduced Light-Evoked Inhibition Increases Rod Pathway Signaling." Association for Research in Vision and Ophthalmology (ARVO), 2016. http://hdl.handle.net/10150/604678.
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Recent studies suggest that the neural retinal response to light is compromised in diabetes. Electroretinogram studies suggest that the dim light retinal rod pathway is especially susceptible to diabetic damage. The purpose of this study was to determine whether diabetes alters rod pathway signaling.
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Kaur, Shilpa. "Role of Wnt signaling in the polarization of neuronal precursors in the C. elegans embryo." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0068.
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Chez les vertébrés et les invertébrés les neurones sont souvent produits par division cellulaire asymétrique. Ce processus est notamment régulé par certains composants de la voie de signalisation Wnt. Cependant, comment les ligands Wnt, des molécules sécrétées activatrices de la voie Wnt, régulent ces divisions n’est pas compris. Le but de ma thèse est d’analyser le rôle des ligands Wnt et de leurs récepteurs dans les divisions asymétriques des précurseurs neuronaux en utilisant C. elegans comme organisme modèle. Chez C. elegans, les précurseurs neuronaux se divisent asymétriquement le long de l’axe antéro-posterieur. Le laboratoire d’accueil a montré que ces divisions sont régulées par un composant nucléaire de la voie Wnt, la beta-caténine, qui s’accumule spécifiquement dans le noyau de la cellule fille postérieure suite à la division asymétrique. Durant ma thèse, j’ai analysé le rôle de composants extracellulaires et corticaux dans ces divisions en utilisant le lignage cholinergique AIY comme lignage test. J’ai tout d’abord observé que les précurseurs neuronaux sont allongés le long de l’axe antéro-postérieur avant leur division. Trois ligands Wnt (CWN-1, CWN-2 et MOM-2) sont transcrits de façon plus importante dans la région postérieure de l’embryon. Via des expériences de perte et gain de fonction j’ai montré que les ligands Wnt régulent l’orientation des divisions ainsi que l’asymétrie d’identité des cellules filles. J’ai également identifié un rôle pour le récepteur de Wnt MOM-5 et la protéine corticale APC au cours des divisions asymétriques. MOM-5 est enrichi au pôle postérieur et APC au pôle antérieur des précurseurs neuronaux avant leur divisionIn both vertebrates and invertebrates neurons are often produced by asymmetric cell divisions. Some components of the Wnt pathway have been implicated in this process. However, how Wnt ligands, secreted activators of the Wnt pathway, regulate these divisions is not understood. The aim of my PhD is to analyze the role of Wnt ligands and of their receptors in neuronal precursor asymmetric divisions using C. elegans as a model organism. In the C. elegans embryo, neuronal precursors divide asymmetrically along the antero-posterior axis. The host laboratory has shown that these asymmetric divisions are regulated by a nuclear component of the Wnt pathway, beta-catenin, which accumulates specifically in the nucleus of the posterior daughter cell following asymmetric cell division. During my PhD, I analyzed the role of extracellular and cortical components in the asymmetric divisions of neuronal precursors using the AIY cholinergic lineage as a test lineage. I first observed that neuronal precursors are elongated along the antero-posterior axis before their division. Three Wnt ligands (CWN-1, CWN-2 and MOM-2) are transcribed at a higher level in the posterior region of the embryo. Using loss and gain of function experiments, I have observed that the Wnt ligands regulate the orientation of the divisions as well as the asymmetry in the identity of the daughter cells. I also identified a role for the Wnt receptor MOM-5 and the cortical protein APC during these asymmetric divisions. MOM-5 is enriched at the posterior pole and APC at the anterior pole of the neuronal precursors before their divisions
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Han, Jing. "ROLE OF THE REGULATOR OF G PROTEIN SIGNALING 2 (RGS2) FOR NEURONAL AND SYSTEM FUNCTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1175703706.
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Brusich, Douglas J. "Dual roles for an intracellular calcium-signaling pathway in regulating synaptic homeostasis and neuronal excitability." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1830.
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Neurons are specialized cells that communicate via electrical and chemical signaling. It is well-known that homeostatic mechanisms exist to potentiate neuronal output when activity falls. Likewise, while neurons rely on excitable states to function, these same excitable states must be kept in check for stable function. However, the identity of molecular factors and pathways regulating these pathways remain elusive.
Chapter 2 of this thesis reports the findings from an RNA interference- and electrophysiology-based screen to identify factors necessary for the long-term maintenance of homeostatic synaptic potentiation. Data is reported to resolve a long-standing question as to the role of presynaptic Cav2-type channels in homeostatic synaptic potentiation at the Drosophila NMJ. It is shown that reduction in Cav2 channel expression and resultant activity is not sufficient to occlude homeostatic potentiation. Thus, the homeostatic block of a amino-acid substituted Cav2-type calcium channel (cacS) channel is presumed to be due to loss of a specific signaling or binding activity, but not due to overall diminishment in channel function. It is also reported that both Drosophila homologs of phospholipase Cβ (PLCβ) and its putative activator Gαq were found to be necessary for a scaling up of neurotransmitter release upon genetic ablation of glutamate receptors. These factors are canonically involved in the activation of intracellular calcium stores through the inositol trisphosphate receptor (IP3R) and the closely related ryanodine receptor (RyR). Likewise, the Drosophila homolog of Cysteine String Protein (Csp) is identified as important for long-term homeostatic potentiation. CSP has also been reported to be involved in regulation of intracellular calcium. PLCβ, Gαq, and CSP are also known to regulate Cav2-type channels directly, and this possibility, as well as others, are discussed as mechanisms underlying their roles in homeostatic potentiation.
Chapter 3 of this thesis reports the extended findings from expression of a gain-of-function Cav2-type channel. The Cav2.1 channel in humans is known to cause a dominant, heritable form of migraine called familial hemiplegic migraine (FHM). Two amino-acid substitutions causative for migraine were cloned into their analogous residues of the Drosophila Cav2 homolog. Expression of these migraine-modeled channels gave rise to several forms of hyperexcitability. Hyperexcitability defects included abnormal evoked waveforms, generation of spontaneous action potential-like events, and multi-quantal release. It is shown that these forms of hyperexcitability can be mitigated through targeted down-regulation of the PLCβ-IP3R-RyR intracellular signaling pathway.
Chapter 4 presents an extended discussion as to the roles for presynaptic calcium channels, PLCβ, and CSP in homeostatic synaptic potentiation, and the mechanism underlying hyperexcitability downstream of gain-of-function Cav2-type channels. The proposed model aims to bridge the involvement of the PLCβ pathway in both homeostatic potentiation and neuronal excitability. Last, the implications for these findings on human disease conditions are elucidated.
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Login, Hande. "Activity-regulated retinoic acid signaling in olfactory sensory neurons." Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Medicinska fakulteten), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-89022.
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The aim of the studies included in the thesis is to better understand the interplay between neuronal activity-dependent gene regulation and the bioactive vitamin A metabolite all-trans-retinoic acid (RA) during postnatal development, refinement and maintenance of precise neuronal connectivity using the olfactory sensory neuron (OSN) in the olfactory epithelium (OE) of genetically modified mice as a model. We show that: Inhibition of RA receptor (RAR)-mediated transcription in OSNs reduces expression of the olfactory cyclic nucleotide-gated (CNG) ion channel, which is required for odorant receptor (OR)-mediated stimulus transduction. This, results in increased OSN death and errors in precise connectivity. The increased cell death may be a consequence of reduced intrinsic excitability and/or reduced influx of Ca2+ ions while the errors in connectivity may be due to altered OR-dependent expression of axonal guidance proteins, such as Kirrel-2 and Neuropilin-1. Expression of the RA catabolic enzyme Cyp26B1 in OSNs is positively regulated by RAR-mediated transcription as well as sensory stimulation in a CNG channel-dependent manner. This shows that neuronal activity and local vitamin A metabolism are parts of novel regulatory feedback loop controlling precise connectivity and neuronal survival. The feedback loop may be a form of homeostatic plasticity in response to global changes in neuronal activity. BACE1, an enzyme is implicated in Alzheimer´s disease, and Cyp26B1 are inversely regulated by CNG channel-dependent sensory stimulation. Cyp26B1 expression is switched on at birth, forms a topographic expression gradient in OE and inhibits BACE1 expression into an inverse counter gradient. Taken together these results reveal a novel neuronal activity-dependent mechanism by which sensory stimuli can shape spatial gene expression via altered RA bioavailability. Increased Cyp26B1 expression stimulates turnover of OSNs during adult neurogenesis by a non-cell-autonomous mechanism. The gradient of Cyp26B1 expression correlates with spatially-regulated diversification of OSNs into subpopulations that express different subsets of OR genes. Cyp26B1 expression influences spatial OR diversification of OSNs by two different mechanisms. In the ventrolateral OE, Cyp26B1 inhibits OR expression by blocking OSN differentiation at a stage that may be associated with the cell intrinsic mechanism regulating OR gene choice. In the dorsomedial OE the expression frequency of some ORs is unaltered while other increases, presumably as a consequence of neuronal activity-dependent competition. A probable function of graded and activity-dependent Cyp26B1 expression is to form a topographic partitioning of the olfactory sensory map into functional domains, which gradually differ from each other with regard to experience-driven plasticity and neurogenic potential along the dorsomedial-ventrolateral axis of OE.
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Fleegal, Melissa A. "Angiotensin II modulation of neuronal intracellular signaling cascades regulates short-term and long-term physiological responses." [Gainesville, Fla.] : University of Florida, 2002. http://purl.fcla.edu/fcla/etd/UFE1001140.
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Koemeter-Cox, Andrew I. "The Role of the Neuronal Primary Cilium in the Modulation of G Protein-Coupled Receptor Signaling." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1408891463.
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Hashmi, Fiza. "EFFECTS OF BRAIN-DERIVED NEUROTROPHIC FACTOR AND ITS SIGNALING PATHWAY ON SENSORY NEURONAL ACTIVATION DURING COLITIS." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3980.
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Visceral hypersensitivity is the heightened response to sensory stimuli. Visceral sensations are transmitted through primary afferent neurons in the dorsal root ganglion (DRG) and the sensitization of the neural pathway leads to modification in spinal ascending and descending neurons. The aim of this investigation is to determine the effects of brain-derived neurotrophic factor (BDNF) and its signaling pathway on sensory neuronal activation during colitis. In order to evaluate this, levels of calcitonin-gene related peptide (CGRP), a neuropeptide marker for nociceptive transmission, and phosphorylated cAMP-response element binding protein (pCREB), a molecular switch in neuronal plasticity, were studied in response to BDNF in vivo and in vitro. Colitis caused an increase in the levels of CGRP and pCREB in thoracolumbar DRG, which was attenuated by BDNF neutralizing antibody and PLC inhibitor, U73122, but not PI3K inhibitor, LY294002. BDNF-induced CGRP expression and CREB activation in DRG culture was also blocked by PLC inhibitor, U73122, but not PI3K inhibitor, LY294002, or MEK kinase inhibitor, PD98059. These results suggest a unique signaling pathway, i.e. the PLC-γ pathway, is mediating BDNF action on sensory neuronal activation during colitis.
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Dian, Emese Emöke. "Application of Cultured Neuronal Networks for Use as Biological Sensors in Water Toxicology and Lipid Signaling." Thesis, University of North Texas, 2004. https://digital.library.unt.edu/ark:/67531/metadc5557/.
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This dissertation research explored the capabilities of neuronal networks grown on substrate integrated microelectrode arrays in vitro to be applied to toxicological research and lipid signaling. Chapter 1 details the effects of chlorine on neuronal network spontaneous electrical activity and pharmacological sensitivity. This study demonstrates that neuronal networks can maintain baseline spontaneous activity, and respond normally to pharmacological manipulations in the present of three times the chlorine present in drinking water. The findings suggest that neuronal networks may be used as biological sensors to monitor the quality of water and the presence of novel toxicants that cannot be detected by conventional sensors. Chapter 2 details the neuromodulatory effects of N-acylethanolamides (NAEs) on the spontaneous electrical activity of neuronal networks. NAEs are a group of lipids that can mimic the effects of marijuana and can be derived from a variety of plant sources including soy lecithin. The most prominent NAEs in soy lecithin, palmitoylethanolamide (PEA) and linoleoylethanolamide (LEA), were tested individually and were found to significantly inhibit neuronal spiking and bursting activity. These effects were potentiated by a mixture of NAEs as found in a HPLC enriched fraction from soy lecithin. Cannabinoid receptor-1 (CB1-R) antagonists and other cannabinoid pathway modulators indicated that the CB1-R was not directly involved in the effects of NAEs, but that enzymatic degradation and cellular uptake were more likely targets. The results demonstrate that neuronal networks may also be a viable platform for the elucidation of biochemical pathways and drug mechanisms of action.
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Traub, Stefanie Andrea [Verfasser]. "Establishment of a human iPS cell-derived neuronal model cell to study synaptic signaling / Stefanie Andrea Traub." Konstanz : KOPS Universität Konstanz, 2020. http://d-nb.info/1206538910/34.
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Dixon, Salazar Tracy Jean. "Major histocompatibility complex class I is a negative regulator of neuronal insulin receptor signaling and hippocampal synapse number." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3386747.
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Thesis (Ph. D.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed Jan. 19, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 65-71).
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Frazier, Hilaree N. "Exploring the Role of Insulin Receptor Signaling in Hippocampal Learning and Memory, Neuronal Calcium Dysregulation, and Glucose Metabolism." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacol_etds/32.
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In the late 90’s, emerging evidence revealed that the brain is insulin-sensitive, highlighted by broad expression of brain-specific insulin receptors and reports of circulating brain insulin. Contemporary literature robustly supports the role of insulin signaling in normal brain function and suggests that insulin-related processes diminish with aging, evidenced by decreased signaling markers, reduced insulin receptor density, and lower levels of insulin transport across the blood-brain barrier. In the context of pathological cognitive decline, clinical trials using intranasal insulin delivery have reported positive outcomes on memory and learning in patients with mild cognitive decline or early-stage Alzheimer’s disease. However, while the importance of insulin and its related actions in the brain are robustly supported, the distinct mechanisms and pathways that mediate these effects remain unclear.
To address this, I conducted a series of experiments exploring the impact of insulin on memory and learning in two models: primary hippocampal cell cultures and the Fisher 344 animal model of aging. These studies attempted to identify relationships between insulin receptor signaling, neuronal gene expression, glucose metabolism, and calcium homeostasis in the hippocampus using either expression of a constitutively active human insulin receptor or administration of intranasal insulin. The following dissertation summarizes this work and provides valuable insights into the potential pathways mediating these relationships. Of note, intranasal studies reported that insulin is able to significantly alter gene expression patterns in the hippocampus of both young and aged rats following chronic, repeated exposure to the ligand. In cell culture, constitutive insulin signaling correlated with significantly elevated neuronal glucose uptake and utilization, as well as with significant alterations in the overall expression and localization of the neuron-specific glucose transporter 3. Interestingly, continued activity of the insulin receptor did not appear to alter voltage-gated calcium channels in hippocampal neurons despite prior evidence of the ligand’s role in other calcium-related processes.
The results reported in this manuscript suggest that in the brain, insulin may be involved in a myriad of complex and dynamic events dependent on numerous variables, such as age, length of the exposure, and/or the insulin formulation used. Nevertheless, this work highlights the validity of using insulin to ameliorate age-related cognitive decline and supports the need for further studies exploring alternative approaches to enhance insulin receptor signaling in the brain.
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Sandberg, Malin. "Calcium dynamics and vesicle-release proteins in a prion-infected neuronal cell line /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-245-4/.
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Karolewicz, Beata, Laurel Johnson, Katalin Szebeni, Craig A. Stockmeier, and Gregory A. Ordway. "Glutamate Signaling Proteins and Tyrosine Hydroxylase in the Locus Coeruleus of Alcoholics." Digital Commons @ East Tennessee State University, 2008. https://dc.etsu.edu/etsu-works/8610.
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It has been postulated that alcoholism is associated with abnormalities in glutamatergic neurotransmission. This study examined the density of glutamate NMDA receptor subunits and its associated proteins in the noradrenergic locus coeruleus (LC) in deceased alcoholic subjects. Our previous research indicated that the NMDA receptor in the human LC is composed of obligatory NR1 and regulatory NR2C subunits. At synapses, NMDA receptors are stabilized through interactions with postsynaptic density protein (PSD-95). PSD-95 provides structural and functional coupling of the NMDA receptor with neuronal nitric oxide synthase (nNOS), an intracellular mediator of NMDA receptor activation. LC tissue was obtained from 10 alcohol-dependent subjects and eight psychiatrically healthy controls. Concentrations of NR1 and NR2C subunits, as well as PSD-95 and nNOS, were measured using Western blotting. In addition, we have examined tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of norepinephrine. The amount of NR1 was lower in the rostral (-30%) and middle (-41%) portions of the LC of alcoholics as compared to control subjects. No differences in the amounts of NR2C, PSD-95, nNOS and TH were detected comparing alcoholic to control subjects. Lower levels of NR1 subunit of the NMDA receptor in the LC implicates altered glutamate-norepinephrine interactions in alcoholism.
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Ladarré, Delphine. "Neuronal polarization shapes the targeting and signaling of G-protein coupled receptors (GPCRs) : type-1 cannabinoid receptors and 5-HT1B serotonin receptors show highly contrasted trafficking and signaling patterns in axons and dendrites." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T070/document.
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L’architecture polarisée des neurones est mise en place est maintenue grâce à un adressage hautement contrôlé de protéines vers l’axone ou vers le compartiment somatodendritique. Parmi ces protéines, les récepteurs aux protéines G (RCPG) neuronaux sont des cibles pharmacologiques clés. Cependant, leur pharmacologie est généralement étudiée dans des lignées cellulaires non polarisées et les résultats obtenus dans ces systèmes ne caractérisent pas correctement les effets physiologiques de l’activation des RCPG présents dans le cerveau. Par conséquent, un des principaux sujets de recherche de notre équipe est de comprendre comment la polarité neuronale influe sur la pharmacologie des RCPG, en étudiant l’un des RCPG les plus abondants dans le cerveau : le récepteur cannabinoïque de type-1 (CB1R). Les études précédentes de notre groupe ont suggéré que CB1R acquiert une polarisation axonale grâce à un adressage transcytotique : après leur synthèse, ces récepteurs apparaissent sur la membrane plasmique somatodendritique d’où ils sont rapidement enlevés par endocytose constitutive puis adressés à la membrane plasmique axonale où ils s’accumulent du fait d’une endocytose réduite. Au début de ma thèse, nous avons directement mesuré cette endocytose différentielle et le transport transcytotique de CB1R en utilisant des neurones de rats mis en culture dans des dispositifs microfluidiques. De plus, nous avons montré que des traitements pharmacologiques prolongés peuvent fortement changer la distribution de RCPG à la surface neuronale. Ces résultats démontrent que l’équilibre endocytotique dépendant du compartiment neuronal, qui est contrôlable pharmacologiquement, est important pour la distribution des RCPG neuronaux. Dans une seconde partie, nous avons étudié si le trafic différentiel de CB1R entre axones et dendrites est corrélé avec une pharmacologie différentielle. CB1R est majoritairement couplé à des protéines de type Gi/o et est connu pour inhiber la production d’AMPc. Nous avons donc développé l’imagerie par Föster Resonance Energy Transfer (FRET) appliqué aux cultures de neurones d’hippocampe de rats afin de mesurer la modulation de la voie de signalisation AMPc/PKA en aval de CB1R endogènes dans l’ensemble des compartiments neuronaux : somata, dendrites, mais aussi dans les axones matures très fins. Nos résultats montrent que CB1R possède une pharmacologie différente entre les dendrites et les axones. Notamment, son activation conduit à une diminution plus forte de l’activité basale de la PKA dans les axones comparé aux dendrites, lié au plus grand nombre de récepteurs présents sur la membrane de ce compartiment. De plus, nous démontrons que, contrairement aux récepteurs axonaux, les CB1R somatodendritiques inhibent constitutivement la voie AMPc/PKA. Cette différence est due à la distribution polarisée de la DAGLipase, l’enzyme synthétisant l’endocannabinoïde principal, le 2-arachidonoyglycerol (2-AG). De plus, l’inhibition pharmacologique de la DAGL modifie l’efficacité de plusieurs agonistes de CB1R dans le compartiment somatodendritique mais pas dans l’axone. Cet effet pourrait être dû à une modulation allostérique. Dans une troisième partie, nous avons étudié si les résultats ci-dessus peuvent être généralisés à d’autres RCPG. Etant donné que l’adressage axonal et la pharmacologie in vitro des récepteurs sérotoninergiques 5-HT1B montrent de fortes similitudes avec ceux de CB1R, nous avons étudié la pharmacologie de ces récepteurs en utilisant la technique de FRET développée précédemment. De façon similaire, nous avons trouvé une pharmacologie différentielle entre l’axone et les dendritesPolarized neuronal architecture is achieved and maintained mainly through highly controlled targeting of proteins to axons versus to the somatodendritic compartment. Among these proteins, neuronal G protein coupled receptors (GPCRs) are key therapeutic targets. However, their pharmacology is generally studied in non-polarized cell lines, and results obtained in such systems likely do not fully characterize the physiological effects of brain GPCR activation. Therefore, a main research subject of our group is to understand how neuronal polarity influences GPCR pharmacology, by studying one of the most abundant GPCR in the brain: the type-1 cannabinoid receptor (CB1R). Previous studies of the group suggested that CB1Rs achieve axonal polarization through transcytotic targeting: after their synthesis, these receptors appear on the somatodendritic plasma membrane from where they are removed rapidly by constitutive endocytosis and then targeted to the axonal plasma membrane where they accumulate due to relatively reduced endocytosis rate. At the beginning of my PhD project we directly demonstrated this differential endocytosis and transcytotic transport of CB1Rs by using cultured neurons in microfluidic devices. Moreover, we showed that chronic pharmacological treatments may strongly change neuronal GPCR distribution on the neuronal surface. These results demonstrate that subdomain-dependent steady-state endocytosis, which is pharmacologically controllable, is important for GPCR distribution in neurons. In a second part, we asked if differential traffic of CB1Rs between axons and dendrites is correlated with differential pharmacology. CB1R is predominantly coupled to Gi/o proteins and is known to inhibit cAMP production. Thus, we developed live Föster Resonance Energy Transfer (FRET) imaging in cultured hippocampal neurons in order to measure basal cAMP/PKA pathway modulation downstream of endogenous CB1Rs in all neuronal compartments: in somata, in dendrites but also in the very thin mature axons. Our results show that CB1R displays differential pharmacology between axon and dendrites. Notably, its activation leads to a stronger decrease of PKA activity in axons compared to dendrites, due to increased number of membrane receptors in this compartment. Moreover, we demonstrate that somatodendritic CB1Rs constitutively inhibit cAMP/PKA pathway, while axonal receptors do not. This difference is due to polarized distribution of DAGLipase, the enzyme that synthesizes the major endocannabinoid 2-arachidonoylglycerol (2-AG). Moreover, blocking DAGL by pharmacological treatment modifies somatodendritic, but not axonal effects of several CB1R agonists, possibly through allosteric action. In a third part, we asked if the above results may be generalized to other GPCRs. Because the axonal targeting and in vitro pharmacology of 5-HT1B serotonin receptors demonstrate strong similarities with CB1Rs, we studied their neuronal pharmacology by using the previously developed FRET technique. We found similar differential responses to pharmacological treatments between axon and dendrites. In a fourth part, we investigated the role of the threonine 210 (T210) residue in the constitutive activity of neuronal CB1R. We showed that the hypoactive mutant T210A-CB1R do not constitutively recruit signaling pathways even in somatodendritic compartment, where 2-AG is present. This result demonstrates that T210 is necessary for constitutive CB1R activation by 2-AG.Finally, previous results of our group demonstrated the involvement of CB1R in neuronal development. Notably, CB1R activation was shown to have an overall inhibitory effect on the development of polarized neuronal morphology. We established a bibliographic review on this subject. The published literature data suggest that not only neuronal polarization influences both CB1R traffic and pharmacology but CB1Rs also contribute to the achievement of neuronal polarization. (...)
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Brumback, Audrey Christine. "Thermodynamic regulation of NKCC1-mediated chloride transport underlies plasticity of GABAA signaling /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2006.
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Thesis (Ph.D. in Neuroscience) -- University of Colorado at Denver and Health Sciences Center, 2006.Typescript. Includes bibliographical references (leaves 86-96). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Alp, Murat. "A kinetic model of calcium binding to calretinin : experimental measurements and predicted effects on calcium signaling at neuronal synapses /." view abstract or download file of text, 2005. http://wwwlib.umi.com/cr/uoregon/fullcit?p3190505.
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Thesis (Ph. D.)--University of Oregon, 2005.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 250 - 269). Also available for download via the World Wide Web; free to University of Oregon users.
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Bhardwaj, Deepshikha. "Phosphorylated Tyr142 β-Catenin signaling in axon morphogenesis and centrosomal functions." Doctoral thesis, Universitat de Lleida, 2014. http://hdl.handle.net/10803/285932.
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β-catenin is a multifunctional protein, key component of adherent junctions and effector of the Wnt canonical pathway, was recently implicated in centrosomal functions. In the canonical Wnt pathway, when Wnt is present in the system, β-catenin escapes degradation, accumulates in the cytosol and translocates to the nucleus where, together with T-cell Factor (TCF) transcription factors, it regulates transcription of Wnt targets. Switching from adhesive to signaling functions (independent of Wnt) is achieved in part through phosphorylation of β-catenin at Tyr142 that promotes detachment of β-catenin from the adhesion complex and promotes migration by transcriptional regulation of target genes. Met receptor tyrosine kinase (the receptor for Hepatocyte Growth Factor (HGF)), is one of the kinases regulating β-catenin phosphoryation at Tyr142 during cell migration and axon outgrowth stimulated by HGF. On the other hand, β-catenin phosphorylation at Ser/Thr regulates β-catenin degradation and has been demonstrated to affect centrosomal cohesion/separation and spindle formation.
Here we focus on PhosphoTyrosine142 β-catenin (PTyr142 β-cat) signaling. First, we demonstrate that chemokines of CC and CXC families promote axon outgrowth. Furthermore, chemokine signaling acts downstream to HGF/Met/β-catenin/TCF signaling to regulate axon morphogenesis in developing hippocampal neurons. We also show that CXCL2 promotes axon branching and is involved in sensory axon outgrowth from dorsal root ganglia. In the second part of the work, we find for the first time that phosphorylated Tyr142 β-catenin localizes to centrosomes in primary astrocytes and glioma cells, and that centrosomal levels drop in mitosis. We also demonstrate the novel centrosomal localization of Met phosphorylated at Tyr1234/35. Aiming at identifying which is the kinase(s) regulating centrosomal PTyr142 β-cat, we show that a Met inhibitor does not affect it. However, an inhibitor of Spleen Tyrosine Kinase (Syk) decreases centrosomal PTyr142 β-cat, suggesting that Syk regulates the phosphorylation of Tyr142 β-catenin at centrosome. In addition, β-catenin is involved in the correct positioning of centrosomes during astrocyte migration and phosphorylation of β-catenin at Tyr142 is needed for HGF-stimulated cell migration.
Collectively, this work demonstrates the multiple roles of PTyr142 β-cat signaling, influencing axon morphogenesis (via regulation of chemokines expression) as well as centrosomal functions, cell polarity and migration.β-catenina es una proteína multifuncional, componente clave de las uniones adherentes y efector de la vía canónica Wnt, recientemente implicada en funciones centrosomales. En la señalización por Wnt, cuando Wnt está presente, β-catenina se acumula en el citosol y transloca al núcleo donde, junto con factores TCF, regula la transcripción de genes diana. La interelación entre funciones adhesivas y señalizadoras (independientes de Wnt) de β-catenina se logra, en parte, a través de la fosforilación de β-catenina en Tyr142, que promueve la desunión de β-catenina del complejo de adhesión y la migración a través de la regulación transcripcional. El receptor tirosina quinasa Met (receptor del Factor de Crecimiento Hepático (HGF)) induce la fosforilación de β-catenina en Tyr142 durante la migración y el crecimiento axonal estimulados por HGF. Por otra parte, la fosforilación de β-catenina en Ser/Thr regula la degradación de β-catenina y afecta a la cohesión/separación de los centrosomas y la formación del huso mitótico. Aquí nos centramos en la señalización por β-catenina fosforilada en Tyr142. En primer lugar, demostramos que quimiocinas de las familias CC y CXC promueven el crecimiento axonal y que las quimiocinas actúan en la señalización inducida por HGF/Met/β-catenina/TCF durante la morfogénesis del axón. También mostramos que CXCL2 promueve la ramificación del axón en neuronas hipocampales y el crecimiento de axones sensoriales de los ganglios de la raíz dorsal. En segundo lugar, demostramos que β-catenina fosforilada en Tyr142 localiza en centrosomas en astrocitos primarios y células de glioma, y que estos niveles centrosomales disminuyen durante la mitosis. También mostramos la localización centrosomal de Met activo. Con objeto de identificar cual es la quinasa que regula la fosforilación de Tyr142 β-catenina en el centrosoma, mostramos que un inhibidor de Syk disminuye los niveles centrosomales de esta forma de β-catenina, lo que sugiere que Syk fosforila β-catenina en Tyr142 en el centrosoma. Además, β-catenina está implicada en el posicionamiento del centrosoma durante la migración de astrocitos y la fosforilación de β-catenina en Tyr142 es necesaria en la migración celular estimulada por HGF. En conjunto, este trabajo ilustra las múltiples funciones señalizadoras de β-catenina fosforilada en Tyr142 en la morfogénesis del axón (a través de la expresión de quimiocinas), así como en funciones centrosomales y en polaridad celular y migración.
β-catenina és una proteïna multifuncional, component clau de les unions adherents i efector de la via canònica Wnt, recentment implicada en funcions centrosomals. En la senyalització per Wnt, quan Wnt està present β-catenina s'acumula en el citosol i transloca al nucli on, juntament amb factors TCF, regula la transcripció de gens diana. La interrelació entre funcions adhesives i funcions senyalitzadores (independents de Wnt) de β-catenina s'aconsegueix en part a través de la fosforilació de β-catenina en Tyr142, que promou la desunió de β-catenina del complex d'adhesió i la migració mitjançant la regulació transcripcional. El receptor tirosina quinasa Met (receptor del Factor de Creixement Hepàtic (HGF)) regula la fosforilació de β-catenina en Tyr142 durant la migració cel · lular i el creixement axonal estimulat per HGF. D'altra banda, la fosforilació de β-catenina en Ser/Thr regula la degradació de β-catenina i afecta la cohesió/separació centrosomal i la formació del fus mitòtic. Aquí ens centrem en la senyalització per β-catenina fosforilada en Tyr142. En primer lloc, demostrem que quimiocines de les famílies CC i CXC promouen el creixement axonal i que la senyalització per quimiocines és necessària en la senyalització induïda per HGF/Met/β-catenina/TCF durant la morfogènesi axonal en neurones de l'hipocamp. També mostrem que CXCL2 promou la ramificació de l'axó i que aquesta quimiocina està involucrada en el creixement d'axons sensorials dels ganglis de l'arrel dorsal. A la segona part, demostrem que β-catenina fosforilada en Tyr142 es localitza en els centrosomes en astròcits primaris i cèl · lules de glioma, i que els seus nivells centrosomals disminueixen durant la mitosi. A més, demostrem la localització centrosomal de Met actiu. Amb l'objectiu d'identificar quina és la quinasa que regula els nivells centrosomals de fosfo-Tyr142 β-catenina, mostrem que un inhibidor de Syk disminueix els nivells centrosomals de fosfo-Tyr142 β-catenina, el que suggereix que Syk fosforila β-catenina en Tyr142 al centrosoma. A més, β-catenina està implicada en el posicionament del centrosoma durant la migració d'astròcits i la fosforilació de β-catenina en Tyr142 és necessària en la migració cel.lular estimulada per HGF. En conjunt, aquest treball demostra les múltiples funcions senyalitzadores de β-catenina fosforilada en Tyr142, en la morfogènesi de l'axó (a través de la regulació de l'expressió de quimiocines), així com en funcions centrosomals i en polaritat cellular i migració.