• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 20
  • 8
  • 5
  • 2
  • 2
  • 2
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • Tagged with
  • 41
  • 41
  • 41
  • 41
  • 9
  • 8
  • 8
  • 8
  • 6
  • 6
  • 5
  • 4
  • 4
  • 4
  • 4
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Glycogen Synthase Kinase 3 Influences Cell Motility and Chemotaxis by Regulating Phosphatidylinositol 3 Kinase Localization in Dictyostelium discoideum

Sun, Tong 06 March 2013 (has links)
Glycogen Synthase Kinase 3 (GSK3), a serine/threonine kinase initially characterized in the context of glycogen metabolism, has been repeatedly realized as a multitasking protein that can regulate numerous cellular events in both metazoa and protozoa. I recently found GSK3 plays a role in regulating chemotaxis, a guided cell movement in response to an external chemical gradient, in one of the best studied model systems for chemotaxis - Dictyostelium discoideum. It was initially found that comparing to wild type cells, gsk3- cells showed aberrant chemotaxis with a significant decrease in both speed and chemotactic indices. In Dictyostelium, phosphatidylinositol 3,4,5-triphosphate (PIP3) signaling is one of the best characterized pathways that regulate chemotaxis. Molecular analysis uncovered that gsk3- cells suffer from high basal level of PIP3, the product of PI3K. Upon chemoattractant cAMP stimulation, wild type cells displayed a transient increase in the level of PIP3. In contrast, gsk3- cells exhibited neither significant increase nor adaptation. On the other hand, no aberrant dynamic of phosphatase and tensin homolog (PTEN), which antagonizes PI3K function, was observed. Upon membrane localization of PI3K, PI3K become activated by Ras, which will in turn further facilitate membrane localization of PI3K in an F-Actin dependent manner. The gsk3- cells treated with F-Actin inhibitor Latrunculin-A showed no significant difference in the PIP3 level. I also showed GSK3 affected the phosphorylation level of the localization domain of PI3K1 (PI3K1-LD). PI3K1-LD proteins from gsk3- cells displayed less phosphorylation on serine residues compared to that from wild type cells. When the potential GSK3 phosphorylation sites of PI3K1-LD were substituted with aspartic acids (Phosphomimetic substitution), its membrane localization was suppressed in gsk3- cells. When these serine residues of PI3K1-LD were substituted with alanine, aberrantly high level of membrane localization of the PI3K1-LD was monitored in wild type cells. Wild type, phosphomimetic, and alanine substitution of PI3K1-LD fused with GFP proteins also displayed identical localization behavior as suggested by the cell fraction studies. Lastly, I identified that all three potential GSK3 phosphorylation sites on PI3K1-LD could be phosphorylated in vitro by GSK3.
22

Synthesis and Characterization of Novel Inhibitors of Glycogen Synthase Kinase 3

Pritchard, Joshua A. 24 September 2020 (has links)
No description available.
23

GSK3: A Neuromodulator of Cocaine-Induced Behavioral Responses

Miller, Jonathan S. January 2009 (has links)
Cocaine is a highly abused psychostimulant with repeated use potential culminating in addiction, a disease associated with compulsive drug seeking, use and high rates of relapse despite adverse consequences. It is well established that cocaine acts by binding to and blocking monoamine transporters therefore increasing synaptic extracellular monoamine concentrations. Cocaine also increases extracellular levels of the excitatory amino acid glutamate within the neural circuitry comprising the ascending dopamine system. Cocaine induces a number of behavioral and neurochemical manifestations following acute and repeated administration. As such, elucidating the molecular mechanisms involved in the behavioral and neuromodulatory effects of cocaine are critical to the development of effective pharmacotherapies for cocaine addiction. The overall aim of this research was to identify a novel kinase that may be involved in the behavioral effects of cocaine. Thus, we chose to investigate glycogen synthase kinase-3 (GSK3), which has recently gained attention as being critical in dopaminergic and glutamatergic signal transduction. GSK3 is a critical mediator of many intracellular signaling systems. The activity of GSK3 is regulated by several kinases including Akt, with inactivation occurring via phosphorylation of the inhibitory serine-21(α-isoform) and serine-9 (β-isoform) residues. It is well established that acute cocaine administration causes hyper-locomotion in animal models and that repeated cocaine administration elicits a sensitized or increased response to the locomotor-stimulating properties of the drug. The studies outlined herein sought to determine whether non-selective and selective inhibition of GSK3 would regulate acute cocaine-induced hyper-locomotion. Further, we investigated the role of GSK3 in the development of cocaine-induced locomotor sensitization. Results of the research outlined herein demonstrate that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long-term neuroadaptations produced by repeated cocaine, therefore suggesting a role for GSK3 in the behavioral manifestations associated with cocaine exposure. Previous studies have assessed the role of the dopamine D1 receptor in locomotor behaviors. As cocaine indirectly activates dopamine D1 receptors, we investigated whether activation of GSK3 was necessary for the expression of dopamine D1 receptor-mediated behaviors. To assess the role of GSK3 in dopamine D1 receptor-induced hyperactivity, GSK3 was inhibited prior to administration of the selective dopamine D1 receptor agonist SKF-82958. Selective inhibition of GSK3 reduced ambulatory and stereotypic activity produced by SKF-82958. These data implicate a role for GSK3 in the behavioral manifestations associated with dopamine D1 receptor activation. To further assess the importance of GSK3 in cocaine-induced behaviors we investigated the role of GSK3 in various facets of cocaine-conditioned reward. We show that selective inhibition of GSK3 prevented the development of cocaine-conditioned reward using a conditioned place preference paradigm, indicating a reduction in the rewarding properties of cocaine. Relapse to drug-seeking can be precipitated by certain stimuli including the drug itself, drug-paired contextual cues and stress. Memory of drug-paired cues is highly resistant to extinction and the molecular mechanisms underlying relapse have not been clearly defined. Our results demonstrate that inhibition of GSK3 interfered with the reconsolidation of cocaine-associated contextual memories by preventing the retrieval of cocaine conditioned place preference. Inhibition of GSK3 in a neutral environment 24 hours prior to the test for reinstatement, however, did not prevent reinstatement of cocaine place preference following a cocaine priming injection. Thus, our results indicate that GSK3 serves an important role in cocaine-conditioned reward and is a critical intracellular signaling protein for the development of cocaine place preference. GSK3 is also essential to the reconsolidation and subsequent retrieval of cocaine-associated contextual cues. In addition to studying the role of GSK3 in cocaine-induced behaviors, we assessed the neuromodulatory effects of cocaine on GSK3 activity. As stated previously, the activity of GSK3 is regulated by a number of kinases including Akt (protein kinase B). Recent evidence suggests that psychostimulants regulate the activity of Akt and subsequently GSK3 in various brain regions. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated. Enzymatic activity was assessed by determining protein phosphorylation in the brain. Mice administered acute injections of cocaine showed a significant decrease in phosphorylated Akt (Thr. 308) and GSK3β; in the caudate putamen as determined by Western blot analysis. Cocaine did not alter pAkt (Thr. 308) or pGSK3β; in the nucleus accumbens or frontal cortex. The role of dopaminergic and glutamatergic receptors on cocaine-induced attenuation of pAkt (Thr. 308) and pGSK3β; was also assessed. Blockade of the dopamine D1, D2 or glutamatergic NMDA receptor prevented cocaine-induced attenuation of pGSK3β; in the caudate putamen. Only blockade of the dopamine D2 receptor prevented the effect of cocaine on pAkt (Thr. 308) levels in the caudate putamen. The results of the present study indicate that the activity of Akt and GSK3 is selectively regulated in the brain following acute cocaine, an effect that is contingent upon both dopaminergic and glutamatergic receptor regulation. In summary, the experiments described in this dissertation tested the initial hypothesis that GSK3 mediates acute cocaine-induced hyperactivity and locomotor sensitization. Acute cocaine administration increased the phosphorylation of GSK3 in the caudate putamen, therefore enhancing kinase activity. Further, the increase in GSK3 activity following cocaine administration is contingent upon activation of the dopamine D1 and D2 receptors and the glutamatergic NMDA receptor. Results presented herein also demonstrate a role for GSK3 in cocaine-conditioned reward. Selective inhibition of GSK3 prevented the development of cocaine conditioned place preference. Inhibition of GSK3 also prevented the retrieval of cocaine contextual memories, therefore playing an important role in reconsolidation. Thus, the results presented in this dissertation indicate that GSK3 is a neuromodulator of cocaine-induced behaviors and may be an important factor underlying cocaine addiction. / Pharmacology
24

Atividade da enzima GSK-3B em pacientes idosos portadores de transtorno bipolar medicados / GSK-3B activity in elderly patients with bipolar disorder undergoing treatment

Ladeira, Rodolfo Braga 30 August 2012 (has links)
Objetivo: A glicogênio sintase quinase-3 beta (GSK-3B) é uma enzima presente em diversos sistemas biológicos e está envolvida na fisiopatologia de vários transtornos neuropsiquiátricos, incluindo o transtorno bipolar. No entanto, estudos in vivo da GSK-3B que envolvam pacientes bipolares são escassos. O objetivo do presente estudo foi avaliar a atividade da GSK-3B em plaquetas de pacientes idosos com transtorno bipolar em tratamento, em comparação com idosos saudáveis não medicados. Métodos: Foram obtidas amostras de plaquetas de 63 idosos (transtorno bipolar=31, grupo controle=32). A atividade enzimática foi estimada pela razão entre a expressão da forma fosforilada (inativa) da GSK-3B em relação à expressão de ambas as formas (ativa e inativa) da enzima (GSK-3B total), que fornece uma estimativa inversa da atividade enzimática (um aumento da razão indica menor atividade da GSK-3B). A intensidade dos sintomas foi avaliada pela Escala de Depressão de Hamilton de 21 itens e pela Escala de Mania de Young, e o desempenho cognitivo foi avaliado pelo Cambridge Cognitive Test e pelo Mini- Exame do Estado Mental. Resultados: A forma fosforilada da GSK-3B (fosfo-GSK-3B) e a razão da GSK-3B estavam elevadas em pacientes com transtorno bipolar, quando comparadas aos idosos do grupo controle (p=0,018 e p=0,016, respectivamente). Na avaliação por subgrupos, observaram-se níveis da fosfo-GSK-3B e da razão da GSK-3B mais elevados nos pacientes com transtorno bipolar em uso de lítio, quando comparados aos controles (p=0,030 e p=0,023, respectivamente), mas não quando comparados aos pacientes com transtorno bipolar que não usavam lítio. O uso das demais medicações avaliadas (anticonvulsivantes, antipsicóticos, antidepressivos e 16 benzodiazepínicos) não estava associado a diferenças na fosfo-GSK-3B ou na razão da GSK-3B, quando comparado aos controles. Conclusões: A atividade da GSK-3B está diminuída no presente grupo de idosos com transtorno bipolar em tratamento medicamentoso. A ausência de um grupo de pacientes com transtorno bipolar não medicado, e a não uniformidade das medicações utilizadas não nos permitem afirmar se essa redução se deve à características da doença bipolar em si ou seria influência dos medicamentos utilizados / Objective: Glycogen synthase kinase-3 beta (GSK-3B) is an important enzyme present in various biological systems and it is involved in the pathophysiology of many prevalent neuropsychiatric diseases, including bipolar disorder. However, human studies addressing GSK-3B activity in vivo are scarce. The aim of the present study was to evaluate GSK-3B activity in platelets of elderly patients with bipolar disorder undergoing clinical treatment as compared to healthy older adults unmedicated. Methods: Platelets samples where obtained from 63 older adults (bipolar disorder=31, comparison group=32). Enzymatic activity was estimated by means of the ratio between the expression of the phosphorylated (inactive) form of GSK-3B to the expression of both forms (active and inactive) of the enzyme (total GSK-3B), yielding an inverse estimate of enzymatic activity (higher ratio indicating lower GSK- 3B activity). The magnitude of mood symptoms was evaluated by the Hamilton Depression Scale and Young Mania Rating Scale, and the cognitive performance was assessed by the Cambridge Cognitive Test and the Mini-Mental State Examination. Results: The phosphorylated form of GSK-3B (phospho-GSK-3B) and the GSK-3B ratio were elevated in patients with bipolar disorder as compared to healthy controls (P=.018 and P=.016, respectively). When analyzed by subgroups, phospho-GSK-3B and the GSK-3B ratio were elevated in bipolar patients undergoing lithium treatment as compared to healthy controls (P=.030 and P=.023, respectively), but not when compared to bipolar patients without lithium treatment. The use of other drugs evaluated (anticonvulsants, antipsychotics, antidepressants and benzodiazepines) was not associated with distinct values of either phospho-GSK-3B or GSK-3B ratio, when compared to controls. 18 Conclusions: GSK-3B activity is decreased in this group of older adults with bipolar disorder undergoing pharmacological treatment. The absence of a group of unmedicated bipolar patients and the non-uniform pattern of treatment do not allow us to say whether this reduction is due to characteristics of bipolar illness itself or an influence of the therapeutic drugs in use
25

Retrograde signaling mechanisms of nerve growth factor regulating the survival and apoptosis of sympathetic neurons

Mok, Sue-Ann Unknown Date
No description available.
26

Retrograde signaling mechanisms of nerve growth factor regulating the survival and apoptosis of sympathetic neurons

Mok, Sue-Ann 11 1900 (has links)
The survival of several neuron populations during development, including sympathetic neurons, is strictly regulated by neurotrophins such as nerve growth factor (NGF) released from innervation targets. NGF activates its receptor, TrkA, at axon terminals, to generate signals that are transmitted retrogradely to cell bodies to induce signaling cascades regulating survival. A general view of this process is that NGF generates retrograde survival signals that, when delivered to cell bodies, induce downstream survival signaling that prevents apoptosis. A retrograde survival signal proposed to be necessary for sympathetic neuron survival consists of endosomes containing NGF and phosphorylated TrkA. For this signal, phosphorylated TrkA arriving at cell bodies is required to initiate survival signaling. Studies have tested the necessity of TrkA phosphorylation in the cell bodies for survival: results from different studies contradict each other. Moreover, the Trk inhibitor, K252a, used in these studies, has reported non-specific effects. Using an alternate Trk inhibitor, Gö6976, data presented in this thesis demonstrates that NGF can promote survival by retrograde signaling that does not require TrkA phosphorylation in the cell bodies. These retrograde signals may be composed of signaling molecules activated downstream of TrkA in axons since pro-survival molecules downstream of TrkA, Akt and CREB, were found activated in the cell bodies/proximal axons. Data presented in this thesis also reveals a fundamentally different mechanism for how NGF promotes sympathetic neuron survival: a retrograde apoptotic signal that is suppressed by NGF. NGF withdrawal from axons induced the “axon apoptotic signal” that was retrogradely transmitted to cell bodies to activate a key pro-apoptotic molecule, c-jun. The axon apoptotic signal, which was blocked by the kinase inhibitors rottlerin and chelerythrine, was necessary for apoptosis in response to NGF deprivation. Evidence GSK3 is involved in generation or transmission of the axon apoptotic signal was provided by experiments with GSK3 inhibitors and siRNA. The axon apoptotic signal discovery refutes the previous view that NGF acting on axon terminals supports survival exclusively by generating retrograde survival signals. The axon apoptotic signal has broad implications for understanding nervous system development and other conditions where neuronal apoptosis occurs, such as neurotrauma and neurodegenerative diseases.
27

Studies of phosphatidylinositol 3 kinase (PI3K) signaling pathway in mammalian ovarian follicle activation and development /

Rajareddy, Singareddy, January 2007 (has links)
Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.
28

Neuroinflammation and Fragile X syndrome regulation by glycogen synthase kinase-3 /

Yuskaitis, Christopher Joseph. January 2009 (has links) (PDF)
Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Sept. 10, 2009). Includes bibliographical references.
29

Atividade da enzima GSK-3B em pacientes idosos portadores de transtorno bipolar medicados / GSK-3B activity in elderly patients with bipolar disorder undergoing treatment

Rodolfo Braga Ladeira 30 August 2012 (has links)
Objetivo: A glicogênio sintase quinase-3 beta (GSK-3B) é uma enzima presente em diversos sistemas biológicos e está envolvida na fisiopatologia de vários transtornos neuropsiquiátricos, incluindo o transtorno bipolar. No entanto, estudos in vivo da GSK-3B que envolvam pacientes bipolares são escassos. O objetivo do presente estudo foi avaliar a atividade da GSK-3B em plaquetas de pacientes idosos com transtorno bipolar em tratamento, em comparação com idosos saudáveis não medicados. Métodos: Foram obtidas amostras de plaquetas de 63 idosos (transtorno bipolar=31, grupo controle=32). A atividade enzimática foi estimada pela razão entre a expressão da forma fosforilada (inativa) da GSK-3B em relação à expressão de ambas as formas (ativa e inativa) da enzima (GSK-3B total), que fornece uma estimativa inversa da atividade enzimática (um aumento da razão indica menor atividade da GSK-3B). A intensidade dos sintomas foi avaliada pela Escala de Depressão de Hamilton de 21 itens e pela Escala de Mania de Young, e o desempenho cognitivo foi avaliado pelo Cambridge Cognitive Test e pelo Mini- Exame do Estado Mental. Resultados: A forma fosforilada da GSK-3B (fosfo-GSK-3B) e a razão da GSK-3B estavam elevadas em pacientes com transtorno bipolar, quando comparadas aos idosos do grupo controle (p=0,018 e p=0,016, respectivamente). Na avaliação por subgrupos, observaram-se níveis da fosfo-GSK-3B e da razão da GSK-3B mais elevados nos pacientes com transtorno bipolar em uso de lítio, quando comparados aos controles (p=0,030 e p=0,023, respectivamente), mas não quando comparados aos pacientes com transtorno bipolar que não usavam lítio. O uso das demais medicações avaliadas (anticonvulsivantes, antipsicóticos, antidepressivos e 16 benzodiazepínicos) não estava associado a diferenças na fosfo-GSK-3B ou na razão da GSK-3B, quando comparado aos controles. Conclusões: A atividade da GSK-3B está diminuída no presente grupo de idosos com transtorno bipolar em tratamento medicamentoso. A ausência de um grupo de pacientes com transtorno bipolar não medicado, e a não uniformidade das medicações utilizadas não nos permitem afirmar se essa redução se deve à características da doença bipolar em si ou seria influência dos medicamentos utilizados / Objective: Glycogen synthase kinase-3 beta (GSK-3B) is an important enzyme present in various biological systems and it is involved in the pathophysiology of many prevalent neuropsychiatric diseases, including bipolar disorder. However, human studies addressing GSK-3B activity in vivo are scarce. The aim of the present study was to evaluate GSK-3B activity in platelets of elderly patients with bipolar disorder undergoing clinical treatment as compared to healthy older adults unmedicated. Methods: Platelets samples where obtained from 63 older adults (bipolar disorder=31, comparison group=32). Enzymatic activity was estimated by means of the ratio between the expression of the phosphorylated (inactive) form of GSK-3B to the expression of both forms (active and inactive) of the enzyme (total GSK-3B), yielding an inverse estimate of enzymatic activity (higher ratio indicating lower GSK- 3B activity). The magnitude of mood symptoms was evaluated by the Hamilton Depression Scale and Young Mania Rating Scale, and the cognitive performance was assessed by the Cambridge Cognitive Test and the Mini-Mental State Examination. Results: The phosphorylated form of GSK-3B (phospho-GSK-3B) and the GSK-3B ratio were elevated in patients with bipolar disorder as compared to healthy controls (P=.018 and P=.016, respectively). When analyzed by subgroups, phospho-GSK-3B and the GSK-3B ratio were elevated in bipolar patients undergoing lithium treatment as compared to healthy controls (P=.030 and P=.023, respectively), but not when compared to bipolar patients without lithium treatment. The use of other drugs evaluated (anticonvulsants, antipsychotics, antidepressants and benzodiazepines) was not associated with distinct values of either phospho-GSK-3B or GSK-3B ratio, when compared to controls. 18 Conclusions: GSK-3B activity is decreased in this group of older adults with bipolar disorder undergoing pharmacological treatment. The absence of a group of unmedicated bipolar patients and the non-uniform pattern of treatment do not allow us to say whether this reduction is due to characteristics of bipolar illness itself or an influence of the therapeutic drugs in use
30

Role of the Glycogen Synthase Kinase 3 for the Retinal Development and Homeostasis / Rôle de la Glycogène Synthase Kinase 3 dans le Développement et l'Homéostasie de la Rétine

Paquet-Durand, François 22 March 2018 (has links)
Les modifications post-traductionnelles (MPTs) permettent un haut degré de régulation de l'expression des gènes en générant une diversité fonctionnelle au niveau du protéome. Dans le système nerveux, les MPTs régulent entre autres des facteurs de transcription permettant une adaptation rapide à un microenvironnement dynamique. Dans ce contexte, je me suis concentrée sur l’étude des Glycogène Synthase Kinases 3 (GSK3s). Elles sont au centre de la régulation de nombreuses voies de signalisation et contrôlent la stabilité de multiples cibles par phosphorylation. Au cours du développement du cerveau, les kinases GSK3 contrôlent la balance entre la prolifération et la différenciation. La dérégulation de l'activité des kinases GSK3 a un rôle clé dans les maladies neurodégénératives du cerveau. En revanche, le rôle important de ces kinases au cours du développement rétinien ainsi que dans les maladies neurodégénératives rétiniennes reste une question ouverte.L'objectif de ma thèse était d'étudier le rôle de ces kinases au cours du développement et de l'homéostasie rétinienne. J’ai montré que l'absence totale de Gsk3α et de Gsk3β très tôt au cours du développement rétinien entraîne une microphtalmie chez l'adulte. Les deux kinases jouent des rôles redondants puisque l'expression d'un seul allèle Gsk3 est suffisante pour prévenir le phénotype de microphtalmie. Cependant, une analyse phénotypique approfondie dans ce contexte génétique (un seul allèle Gsk3) a révélé une forte augmentation du nombre de cellules ganglionnaires déplacées (dRGCs) dans la couche nucléaire interne, associée à une modification des projections axonales des cellules ganglionnaires dans le cerveau par rapport aux contrôles. Dans l’ensemble, ces données suggèrent que les kinases GSK3s sont essentielles au maintien des progéniteurs rétiniens et sont impliquées dans la genèse des dRGCs. Compte tenu du très faible nombre de dRGCs en conditions normales, la fonction de ces cellules a été très peu étudiée à ce jour. Le modèle génétique que j’ai développé offre par conséquent un modèle de choix pour étudier l’ontogenèse et la fonction de ces cellules.Mes travaux de thèse se sont ensuite concentrés sur le rôle de GSK3 dans les photorécepteurs. En effet, des défauts de développement ou leur mort est l’une des principales causes de dégénérescence rétiniennes. Afin de mieux comprendre la fonction de ces kinases dans la maintenance des photorécepteurs, j'ai donc utilisé des souris invalidées de manière conditionnelle pour Gsk3α et Gsk3β spécifiquement dans les précurseurs des photorécepteurs. L’absence de GSK3 conduit à une altération de la maturation et de la fonction des photorécepteurs, suivie de leur dégénérescence. J’ai alors combiné des analyses transcriptomiques et des approches in vitro pour élucider les mécanismes sous-jacents. Mes données m’ont conduit à proposer un modèle selon lequel l’absence de GSK3 dans les photorécepteurs conduit à des défauts de phosphorylation de NRL (facteur de transcription nécessaire au développement des photorécepteurs de type bâtonnet), augmentant sa stabilité. Cette dérégulation post-traductionnelle conduit à la diminution d’expression d'un sous-ensemble de gènes cibles de NRL, co-régulés par CRX, et impliqués dans le développement et l'homéostasie des photorécepteurs. Cette dérégulation conduirait alors à la dégénérescence des photorécepteurs observée dans les mutants GSK3. Ce travail suggère donc que GSK3 joue un rôle essentiel dans la régulation de NRL pour contrôler la maturation et l'homéostasie des photorécepteurs. De telles données suggèrent également que ce mécanisme de régulation pourrait être déficient chez les patients atteints de rétinites pigmentaires dues à des mutations de NRL empêchant sa phosphorylation par GSK3. / Post-translational modifications (PTMs) allow a higher degree of regulation for the control of gene expression by generating functional diversity at the proteome level. In the central nervous system, PTMs regulate stability or activity of transcription factors allowing a rapid response to external signals and a quick adaptation to a dynamic cellular microenvironment. In this context, I focused on the ubiquitously expressed and highly conserved Glycogen Synthase Kinases 3 (GSK3s). They are at the crossroad of multifunctional signalling pathways. During mammalian brain development, GSK3 kinases control the balance between proliferation and differentiation. Deregulation of GSK3 kinases activity has also a key role in neurodegenerative diseases by causing the accumulation/aggregations of proteins causing neuronal cell death. Drugs targeting GSK3s hold a lot of promises to treat such diseases. Whether these kinases are also important during retinal development and involved in retinal diseases remains an open question. Several studies suggest the importance of regulating GSK3 function in photoreceptor under pathological conditions. Therefore, the main objective of my PhD was to investigate the role of these kinases during photoreceptor development and homeostasis. To better understand the role of these two kinases during retinal development and to highlight potential differences with the developing brain, we also investigated their function in the control of the balance between proliferation and differentiation of retinal progenitors. To achieve my work, I used conditional knockout mice for Gsk3α and Gsk3β specifically deleted either in photoreceptor precursors or in retinal progenitors during early development. The lack of GSK3 kinases in photoreceptor precursors led to impaired photoreceptor maturation and function followed by their degeneration. Transcriptomic analysis (RNAseq) 6, 10 and 14 days postnatally prior degeneration revealed several genes downregulated belonging to biological processes involved in eye development and visual functions. Among them, the expression of the transcription factor Nrl that is required for rod photoreceptor development was decreased. Astonishingly, NRL expression was highly increased at protein level. By in vitro approaches, I demonstrated that GSK3-dependent phosphorylation regulates NRL protein stability. Despite such increase, a large number of NRL target genes were downregulated leading to impaired photoreceptor maturation and function. Surprisingly, a vast majority of these downregulated genes were also target genes for CRX, another transcription factor working in synergy with NRL. This work demonstrates that PTMs of NRL play a critical role in fine tuning the expression of a subset of genes involved photoreceptor development and homeostasis. Such findings could allow the development of innovative therapeutic strategies for retinal dystrophies. The functional characterisation of GSK3 in the course of retinal development by invalidating both Gsk3α and Gsk3β in retinal progenitors early during development revealed their requirement for controlling cell cycle exit and neuronal differentiation. Indeed, the complete lack of Gsk3α and Gsk3β led to microphtalmia in adults. Interestingly, the expression of only one Gsk3 allele was enough to rescue the phenotype. However, further analysis revealed a large number of displaced ganglion cells in the inner nuclear layer. The function of these cells remains to be determined, but their timing of production corresponds to other ganglion cells. Strikingly, these displaced ganglion cells project in distinct brain regions than normal ganglion cells. Therefore, our work could provide the first step toward determining the function of the displaced ganglion cells, which appear at low number in wildtype but whose function remains to be clarified.

Page generated in 0.105 seconds