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Hayashi, Junya. „Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain“. Kyoto University, 2006. http://hdl.handle.net/2433/135623.
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2
Chapman, Heather M. „Gsx genes control the neuronal to glial fate switch in telencephalic progenitors“. University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1394725163.
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3
Larrosa, Madeleine Julie [Verfasser]. „The function of the zinc finger transcription factor Insm1 in neuronal progenitors / Madeleine Larrosa“. Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1219508306/34.
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Larrosa, Madeleine [Verfasser]. „The function of the zinc finger transcription factor Insm1 in neuronal progenitors / Madeleine Larrosa“. Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1219508306/34.
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5
Hyroššová, Petra. „Not to be picky: PEPCK-M ensures metabolic flexibility in cancer cells and neuronal progenitors“. Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/672607.
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Phosphoenolpyruvate carboxykinase (PEPCK) is an enzyme that catalyses decarboxylation of oxaloacetate to phosphoenolpyruvate and it is part of gluconeogenic/glyceroneogenic pathway. There are two known isoforms of PEPCK, the mitochondrial and the cytosolic isozyme that are catalysing chemically identical reactions, but they differ in regulation and expression pattern. Selective presence of mitochondrial isoform of this enzyme (PEPCK-M, PCK2) in all types of cancer examined and in cycling neuroprogenitors, suggests a functional relationship with the metabolic adaptations of these cells. This thesis has had as its main objectives the characterization of the role of PEPCK-M in tumour cells and in neuronal progenitor cells.
Metabolism of cell in CNS is not completely elucidated yet. Here we demonstrate that Tbr2 positive neuronal progenitors are metabolically dependent on lactate, which is favouring maintenance of their undifferentiated state. Lactate as metabolite can feed anabolic pathways and sustain ATP production by its oxidation in the TCA cycle. However, essential pathways like PPP, glycerol synthesis or one carbon metabolism pathways require carbons to feed the glycolytic intermediate pool. PEPCK-M in this setting, with lactate as sole carbon source is the only known pathway to fulfil the above-mentioned anabolic requirements. By using inhibitor of PEPCK-M we were able to prove that Tbr2 positive neuronal progenitors are metabolically dependent on PEPCK-M activity and their number significantly decrease after inhibiting PEPCK-M in vitro and in vivo.
PEPCK-M activity in tumour cells is necessary for survival and growth in 2D and in cultures on semi-solid agar (anchorage-independent growth), which suggests that this enzyme has a fundamental role in the survival program to cell stress. A Kaplan-Meier analysis from datasets available in the GEO database (> 5000 patients) shows that elevated PCK2 expression is significantly associated with a worse prognosis in patients with breast cancer. Despite its potential relevance for metabolic adaptations in cancer, the mechanisms responsible for its pro- survival activity are not known. Therefore, we have proposed to study these mechanisms through metabolomic analysis where we wanted to examine whether PEPCK-M feeds an alternative pathway to glucose using carbons from glutamine in an experimental model with reduced and overexpressed levels of PEPCK-M activity. We demonstrated the functionality of PEPCK-M driven cataplerosis in MCF7 cells grown under glucose deprivation by showing synthesis of serine and glycine from glutamine by observing contribution of 13C-labeled carbons from [U-13C] glutamine into these metabolites. In the absence of nutritional stress (high abundance of glucose and amino acids), the silencing of PEPCK-M induces oxidative stress and the accumulation of succinate, with the consequent induction of p21 and deficiencies in cell growth. Glutamine cataplerosis is not affected by alterations in PEPCK-M activity. However, a higher enrichment of all carbons with 13C in intermediates of the Krebs cycle (TCA cycle) suggests a reduction in flux through this pathway. Together, these data increase our understanding of metabolic adaptations in tumours and the role of PEPCK in providing alternative carbon fluxes to deal with nutritional stress. Finally, these studies allow us to propose PEPCK-M as a new target for the treatment of tumorigenic processes that will need to be validated in the future.El fosfoenolpiruvato carboxiquinasa mitocondrial (PEPCK-M; PCK2) se regula transcripcionalmente por limitación de aminoácidos y por ER-estrés, de una manera dependiente de ATF4, aumentando así la supervivencia de la célula. La presencia selectiva de esta isoenzima en todos los tipos de cáncer examinado y en células neuroprogenitoras, sugiere una relación funcional con las adaptaciones metabólicas de estas células. Esta tesis ha tenido como objetivos fundamentales la caracterización del rol de la PEPCK-M en célula tumoral y en célula neuroprogenitora En cultivos neuronales, los neuroprogenitores Tbr2 positivos requieren lactato como sustrato metabólico para el mantenimiento de su fenotipo y su metabolismo. La PEPCK-M se expresa a niveles altos en este tipo celular y su actividad es necesaria para mantener la viabilidad de estos progenitores y cumplir con los requerimientos anabólicos a partir de carbonos provenientes del lactato. La actividad PEPCK-M en célula tumoral es necesaria para la supervivencia y crecimiento. A pesar de su potencial relevancia para las adaptaciones metabólicas en cáncer, no se conocen los mecanismos responsables de su actividad pro-supervivencia. Por ello, nos hemos propuesto estudiar estos mecanismos mediante análisis de metabolómica con los que hemos querido examinar si la PEPCK-M alimenta una vía alternativa a la glucosa utilizando carbonos provenientes de glutamina en un modelo experimental con niveles de actividad PEPCK-M reducidos y sobreexpresados. La contribución de carbonos marcados con 13C a partir de [U- 13C] glutamina en los productos de ramificación de glicolisis como serina y glicina, esta correlacionando directamente con los niveles de actividad PEPCK-M en condiciones de estrés nutricional (baja glucosa). La cataplerosis de glutamina no se ve afectada por alteraciones en la actividad de PEPCK-M. Sin embargo, un mayor enriquecimiento de 13C en intermediarios del ciclo de Krebs sugieren una reducción del flujo a través de esta vía. En conjunto, estos datos aumentan nuestra comprensión de las adaptaciones metabólicas en los tumores y el papel de la PEPCK en la provisión de flujos de carbono alternativas para lidiar con el estrés nutricional. Finalmente, estos estudios nos permiten proponer a la PEPCK-M como una nueva diana para el tratamiento de procesos tumorogénicos que necesitará ser validada en el futuro.
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WACLAW, RONALD RAYMOND. „MOLECULAR CONTROL OF NEURONAL DIVERSITY IN LATERAL GANGLIONIC EMINENCE PROGENITORS OF THE EMBRYONIC MOUSE TELENCEPHALON“. University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1130334258.
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Belmonte, Mateos Carla 1992. „Unveiling the molecular and behavioral properties of hindbrain rhombomere centers“. Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2022. http://hdl.handle.net/10803/673433.
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Precise regulation of neurogenesis is achieved by differentially allocating the neurogenic competence along the tissue. In the hindbrain proneural gene expression is stereotypically confined in segment boundary-adjacent regions, hence, being absent in segment centers. This segregation of proneural gene expression therefore hints rhombomere centers as a putative non-neurogenic population.
In this work, we unveil their spatiotemporal molecular profile as well as one of the mechanisms involved in their maintenance as non-committed progenitors. By 4D imaging we shed light for the first time into the in vivo cell behavior this population displays. We propose this population in rhombomere centers is indeed heterogeneous as it harbors cells with different proliferative capacity.La regulació precisa de la neurogènesi s’aconsegueix localitzant la competència neurogènica de manera diferencial al llarg del territori. Al cervell posterior, l’expressió de gens proneurals es restringeix a les zones adjacents a les cèl·lules de les fronteres, i per tant és absent als centres així doncs assenyalant els centres dels rombòmers com una població no neurogènica. En aquest treball, hem revelat el seu perfil molecular espai-temporal així com un dels mecanismes que manté aquestes cèl·lules com a no neurogèniques. Mitjançant imatges 4D hem aportat llum per primera vegada a l’enteniment del seu comportament cel·lular en viu, i proposem que aquesta població dels centres dels rombòmers és de fet heterogènia ja que conté cèl·lules amb diferent capacitat proliferativa.
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Tayel, Sara [Verfasser], Marius [Gutachter] Ader und Frank [Gutachter] Buchholz. „Identifiying Casc15 as a novel regulator of progenitors’ proliferation and neuronal migration in the developing neocortex / Sara Tayel ; Gutachter: Marius Ader, Frank Buchholz“. Dresden : Technische Universität Dresden, 2021. http://d-nb.info/123184616X/34.
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McLaughlin, Heather Ward. „Modeling sporadic Alzheimer's disease using induced pluripotent stem cells“. Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13094355.
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Despite being the leading cause of neurodegeneration and dementia in the aging brain, the cause of Alzheimer's disease (AD) remains unknown in most patients. The terminal pathological hallmarks of abnormal protein aggregation and neuronal cell death are well-known from the post-mortem brain tissue of Alzheimer's disease patients, but research into the earliest stages of disease development is hindered by limited model systems. In this thesis, an in vitro human neuronal system was derived from induced pluripotent stem (iPS) cell lines reprogrammed from dermal fibroblasts of AD patients and age-matched controls. This allows us to investigate the cellular mechanisms of AD neurodegeneration in the human neurons of sporadic AD (SAD) patients, whose development of the disease cannot be explained by our current understanding of AD. We show that neural progenitors and neurons derived from SAD patients show an unexpected expression profile of enhanced neuronal gene expression resulting in premature differentiation in the SAD neuronal cells. This difference is accompanied by the decreased binding of the repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) transcriptional inhibitor of neuronal differentiation in the SAD neuronal cells. The SAD neuronal cells also have increased production of \(amyloid-\beta\) and higher levels of tau protein, the main components of the plaques and tangles in the AD brain.
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Voltes, Cobo Adrià 1991. „Hindbrain boundaries : addressing the crossroad between tissue segmentation and cell fate regulation“. Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/665625.
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The hindbrain boundary cell population (BCP) is specified at the interface between adjacent compartments during embryonic development of the posterior brain. Hindbrain BCP is a non-neurogenic population that acts as both a signaling center and an elastic mesh that prevents cell intermingling between adjacent compartments. Remarkably, boundary cells display mechanical characteristics that emphasize the impact of tissue segmentation on boundary architecture: they display specific cell morphology and contain actomyosin cable-like structures that provide the boundaries with the tension necessary for carrying out their physical barrier role.
Considering the mechanical microenvironment in the BCP and its identity specificities, we propose YAP/TAZ-TEAD activity as the molecular scaffold that underpins the crossroad between hindbrain segmentation and proliferative capacity modulation. In this work we show that mechanical stimuli in the BCP trigger YAP/TAZ-TEAD activity. In turn, this activity is responsible for transiently modulating the proliferative capacity of boundary cells, which eventually differentiate into neurons.La població cel·lular de les fronteres del romboencèfal (PCF) s’especifica a la interfície entre compartiments adjacents durant el desenvolupament embrionari del cervell posterior. La PCF del romboencèfal és una població no neurogènica que actua com a centre senyalitzador i com a barrera elàstica que evita la barreja de cèl·lules entre compartiments adjacents. Cal destacar que les cèl·lules de les fronteres presenten característiques mecàniques que fan palès l’impacte de la segmentació del teixit sobre l’arquitectura de les fronteres: presenten una morfologia cel·lular específica i contenen estructures d’actomiosina de tipus cable que proporcionen a les fronteres la tensió necessària per portar a terme la funció de barrera física. Considerant el microambient mecànic a la PCF i les seves especificitats en termes d’identitat, proposem l’activitat YAP/TAZ-TEAD com la bastida molecular present a la intersecció entre la segmentació del romboencèfal i la modulació de la capacitat proliferativa. En aquesta investigació demostrem que els estímuls mecànics presents a la PCF desencadenen l’activitat YAP/TAZ-TEAD. Al seu torn, aquesta activitat és transitòriament responsable de la modulació de la capacitat proliferativa de les cèl·lules de les fronteres, les quals acabaran diferenciant-se en neurones.
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Zaidi, Donia. „Étude des mécanismes pathogéniques dépendants des microtubules dans les progéniteurs neuronaux conduisant aux malformations corticales“. Electronic Thesis or Diss., Sorbonne université, 2023. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2023SORUS159.pdf.
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Les cellules de glie radiaire apicale (RG) sont des cellules clés du développement cortical, capables d'auto-renouvellement ou de génération neuronale, possédant un noyau restreint à la zone ventriculaire (VZ) qui migre en fonction des phases du cycle cellulaire via un phénomène nommé migration nucléaire intercinétique (MNI). Les RG ont une forme bipolaire, avec un long processus basal soutenant la migration neuronale et un court processus apical faisant face au ventricule où un cil primaire (PC), ancré à un centrosome modifié (‘corps basal’), émerge et sert de plateforme de signalisation. Des mutations génétiques peuvent altérer le fonctionnement des RG, affectant le développement cortical et conduisant à des malformations corticales. Ces malformations sont associées chez les patients à de l’épilepsie et à des déficiences intellectuelles. Il est donc important de déterminer comment les processus moléculaires et cellulaires mis en jeu au niveau des RG peuvent être perturbés par des mutations génétiques. Mon travail de thèse a porté sur l’étude de deux gènes mutés conduisant à deux malformations corticales rares. Tout d’abord, le gène codant pour la chaine lourde de la protéine motrice dynéine (DYNC1H1) a été retrouvé muté chez des patients présentant une malformation corticale complexe avec une microcéphalie (petit cerveau) et une dysgyrie (défauts de gyrifications). Lors de mon travail de thèse, j’ai étudié les RG à la mi-corticogenèse dans un modèle murin Knock-In (KI) pour ce gène, reproduisant une mutation faux sens retrouvée chez un patient, en le comparant avec un modèle murin muté pour ce même gène mais conduisant à des neuropathies périphériques. Nous avons découvert des anomalies de MNI, de cycle cellulaire et de migration neuronale. Également, des défauts d’organelles tels que les mitochondries et l’appareil de Golgi ont été identifiés dans les RG, et sont spécifiques à la mutation faux-sens conduisant à la malformation corticale. Deuxièmement, l'hétérotopie sous-corticale (SH) est une malformation caractérisée par la présence anormale de neurones dans la substance blanche. Le gène codant pour EML1 (Echinoderm microtubule associated protein like 1) a été retrouvé muté chez certains patients SH. Lorsqu’Eml1 est muté chez la souris, une proportion de RG se retrouvent en dehors de la VZ, suggérant qu’elles se détachent coté apical. Au niveau apical, des anomalies de PC et des corps basaux ont été décrits. En étudiant un nouveau modèle de souris mutant, inactivé pour Eml1, mon travail s'est concentré sur les altérations subcellulaires et cellulaires des RG afin de comprendre les mécanismes pathogéniques conduisant à leur détachement et donc à la formation de SH. Etudiant les RG en interphase, en analysant les centrosomes, j’ai déterminé que leur structure est affectée dans les cellules de patients et de souris mutante, et ces défauts sont résolus par la stabilisation des microtubules. Le recrutement de protéines aux centrosomes est altéré et la protéine centrosomale Cep170 s'est avérée être un partenaire d'interaction spécifique d’EML1, cette interaction étant perdue quand EML1 présente une mutation SH. Les centrosomes et le PC étant intimement liés au cycle cellulaire, j’ai poursuivi par l'analyse du cycle cellulaire des RG et identifié des altérations de sa cinétique à deux stades de développement. Le séquençage de l'ARN des cellules uniques a permis d'identifier des dérèglements dans l'expression des gènes du cycle cellulaire. Le détachement anormal des RG est plus massif au début du développement que plus tard, ce qui suggère que les altérations de centrosomes et du cycle cellulaire à ce stade peuvent être en amont du détachement anormal des RG. Mon travail de thèse apporte ainsi de nouveaux éléments essentiels à la compréhension des mécanismes altérés dans les progéniteurs neuronaux dans le contexte de malformations corticales raresIn mammals, cortical development is a finely regulated process that leads to the formation of a functional cortex. Apical radial glial cells (RG) are key progenitor cells du ring cortical development, capable of self-renewal or neuronal generation, with a soma restricted to the ventricular zone (VZ) in rodents. Their nucleus migrates according to the phases of the cell cycle by a process called interkinetic nuclear migration (INM). RG have a bipolar shape, with a long basal process supporting neuronal migration and a short apical process facing the ventricle where a primary cilium (PC), anchored to a modified centrosome (‘basal body’), emerges and detects molecules present in the embryonic cerebrospinal fluid. Genetic mutations can alter the function of RG, affecting cortical development and leading to cortical malformations. These malformations are associated in patients with epilepsy, intellectual disabilities and also neuropsychiatric disorders. It is therefore important to determine how the molecular and cellular processes involving RG can be disrupted by genetic mutations. Thus, my thesis work focused on the study of mutations affecting two different genes in the context of two rare cortical malformations. First, the gene encoding for the motor protein dynein heavy chain (DYNC1H1) was found mutated in patients with a complex cortical malformation associated with microcephaly (small brain) and dysgyria (gyri defects). We generated a Knock-In (KI) mouse model for this gene, reproducing a missense mutation found in a patient. During my thesis, I studied RG at mid-corticogenesis of this KI model and, by comparing it with a mouse model mutant for the same gene but leading to peripheral neuropathies, we showed RG alterations specific to the KI model. We found abnormalities in INM, cell cycle and neuronal migration. Also, defects of key organelles, such as mitochondria and Golgi apparatus were identified in progenitors and are specific in the cortical malformation KI model. Secondly, subcortical heterotopia (SH) is a cortical malformation characterized by the abnormal presence of neurons in the white matter. Mutations in the gene coding for EML1 (Echinoderm microtubule associated protein like 1) were identified in certain SH patients. When Eml1 is mutated in mice, numerous RG are found in basal positions of the cortical wall outside the VZ, suggesting that they detach apically. Within the apical process, abnormal PC formation and basal bodies were described. By studying a new mutant mouse model where Eml1 is inactivated, my work focused on subcellular and cellular alterations of RG to understand the pathogenic mechanisms leading to their detachment and thus to SH formation. In interphase RG, focusing on mechanisms upstream of PC formation, I analyzed centrosomes and determined that their structure is affected in patient and mouse mutant cells, and these defects are rescued by stabilizing microtubules. Recruitment of key centrosomal proteins is altered early in development, and the centrosomal protein Cep170 was found to be a specific interacting partner of EML1, this interaction being lost when EML1 carries a patient mutation. Because centrosomes and cilia are intimately linked to the cell cycle, I proceeded to analyze the RG cell cycle and identified alterations in cell cycle kinetics during early and mid-development. Single-cell RNA sequencing at two key developmental stages identified deregulations in cell cycle gene expression. Abnormal RG detachment appears greater in early compared to mid-development, suggesting that centrosomal and cell cycle alterations at this stage may be upstream of abnormal RG detachment. My thesis work thus brings new elements essential to the understanding of the altered mechanisms in neural progenitors related to rare cortical malformations
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Beyko, Sandy. „Neuronal progenitor enrichment in the adult Cx32 knockout (KO) mouse“. Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9354.
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The connexin (Cx) family of channel-forming proteins is comprised of 15 or more members that form intercellular channels directly connecting the cytoplasm of adjacent cells (gap junctions). Cx proteins are found in both oligodendrocytes and neurons in the central nervous system (CNS) and myelinating Schwann cells in the peripheral nervous system (PNS). In humans, mutations in the gap junction Cx32 gene are associated with a inherited demyelinating disorder of the PNS, Charcot-Tooth-Marie disease (CMTX). In the CNS, Cx32 is one of the predominant Cxs expressed during the later stages of differentiation, neurogenesis, cell migration, and neural circuit formation. Thus, it is hypothesized that intracellular communication via Cx32-mediated channels plays a role in regional specification and arrangement of structures within the CNS. However, the impact of endogenous Cx32 expression and/or null mutation on neuronal differentiation have yet to be determined. To test the hypothesis that Cx32 expression influences CNS development, the cerebral development of Cx32 knockout (KO) mice was compared to that of wild-type (WT) littermate controls. (Abstract shortened by UMI.)
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Zanini, Marco. „Ciliogenesis Control Mechanisms in Cerebellar Neuron Progenitors“. Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS475/document.
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Pendant le développement du cervelet, les progéniteurs des neurones granulaires (PNG) nécessitent la présence du cil primaire pour proliférer en réponse à Sonic Hedgehog (SHH). En effet, la prolifération dérégulée des PNGs peut conduire à la formation d'une tumeur pédiatrique maligne appelée SHH-médulloblastome (MB), de ce fait comprendre comment le cil primaire est régulé dans les PNGs est crucial.Nous montrons que le facteur de transcription Atoh1 contrôle la présence du cil primaire dans les PNGs in vitro et in vivo. En particulier, la suppression du cil primaire par l’inactivation génétique de gènes impliqués dans la ciliogenèse (par exemple, Kif3a ou Ift88) empêche Atoh1 de maintenir les PNGs en prolifération, ce qui indique qu’Atoh1 favorise l’expansion des PNGs en maintenant la présence du cil primaire. D’un point de vue moléculaire, Atoh1 contrôle la formation du cil primaire en régulant le bon positionnement peri-centrosomal des satellites centriolaires (SC), complexes protéiques essentiels pour la ciliogenèse. L'inactivation de Atoh1 dans les PNGs perturbe en effet la distribution subcellulaire des SCs, altérant ainsi inévitablement la ciliogenèse. Cette nouvelle fonction de Atoh1 est gouvernée par la régulation transcriptionnelle directe d'un composant clé des SCs, Cep131. L’expression ectopique de Cep131 dans les PNGs restore les effets liés à l'inactivation d'Atoh1, rétablissant la localisation correcte du SC et comme conséquence la présence d’un cil primaire.De plus, nous avons montré que cette voie Atoh1-SC-cil primaire-SHH contrôlant la prolifération des PNGs est également conservée dans le contexte du SHH-MB, où Atoh1 est surexprimée et essentielle pour sa formation et sa maintenance.Ces données révèlent un mécanisme par lequel la ciliogenèse est régulée dans des progéniteurs de neurones, offrant de nouvelles informations sur la neurogenèse dans le cervelet et sur la pathogenèse du SHH-MBCerebellar granule neuron progenitors (GNPs) require the primary cilium to proliferate in response to Sonic Hedgehog (SHH) during cerebellar development. As aberrant proliferation of GNPs may lead to SHH-type medulloblastoma (SHH-MB), a pediatric brain tumor, understanding which mechanisms control ciliogenesis in GNPs represents a major interest in the field. Here, we show that the proneural bHLH transcription factor Atoh1 controls the presence of primary cilia in GNPs both in vitro and in vivo, thus maintaining GNPs responsive to the mitogenic effects of SHH. Indeed, loss of primary cilia induced via knockdown of specific ciliary components (e.g. Kif3a and Ift88) abolishes the ability of Atoh1 to keep GNPs in proliferation in vivo. Mechanistically, Atoh1 controls ciliogenesis by regulating the proper peri-centrosomal clustering of centriolar satellites (CS), large multiprotein complexes working as essential machineries for ciliogenesis. Knockdown of Atoh1 in GNPs perturbs CS subcellular distribution, leading to impairment of ciliogenesis. Luciferase reporter assays and chromatin immunoprecipitation experiments indicate that Atoh1 can directly regulate the expression of Cep131, a key CS core component. Importantly, ectopic expression of Cep131 in GNPs depleted of Atoh1, is sufficient to restore proper CS localization and consequent primary cilia formation, indicating that the Atoh1-Cep131-CS axis is responsible for ciliogenesis in GNPs.In addition, we further demonstrated that these functions of Atoh1 are conserved in the context of SHH-MB, where Atoh1 is typically overexpressed and acts as a lineage-dependent transcription factor.These data reveal a mechanism whereby ciliogenesis is regulated in neuron progenitors providing novel insights into cerebellar neurogenesis and pathogenesis of SHH-MB
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Otsuka, Toshiyuki. „Regulated expression of neurogenic basic helix-loop-helix transcription factors during differentiation of the immortalized neuronal progenitor cell line HC2S2 into neurons“. Kyoto University, 1998. http://hdl.handle.net/2433/182245.
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Gálvez, García Héctor 1989. „The regulation of Atonal 1 and the origin of hair cells in the inner ear“. Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/565808.
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The vertebrate inner ear is the organ responsible for the senses of balance, acceleration and audition. Three cell types form the functional unit of the ear: hair cells, neurons and supporting cells. Atoh1 and Neurog1, two bHLH genes, drive differentiation of hair cells and neurons, respectively. Hair cell and neuronal competence is established early in development. However, hair cell differentiation is delayed with respect to neurons. In this work, I provide evidence for a molecular mechanism that underlies the repression of Atoh1 by Neurog1. Neurog1 is able to reduce the levels of Atoh1 protein and as a consequence, Atoh1 cannot activate its own expression. This provides a novel mechanism for bHLH interactions by which neurons are forced to develop before hair cells during embryonic development.El oído interno de los vertebrados es el órgano responsable de los sentidos del equilibrio, la aceleración y la audición. La unidad funcional del oído está formada por tres tipos celulares: células ciliadas, neuronas y células de soporte. Atoh1 y Neurog1, son genes bHLH que dirigen la diferenciación de las células ciliadas y las neuronas, respectivamente. La competencia para desarrollar células ciliadas y neuronas se establece tempranamente en el desarrollo, sin embargo, la diferenciación de las células ciliadas se retrasa con respecto a la de las neuronas. Este trabajo analiza los mecanismos moleculares que subyacen a la represión de Atoh1 por Neurog1. Los resultados muestran que Neurog1 es capaz de reducir los niveles de proteína de Atoh1 y, en consecuencia, evita que éste active su propia expresión. Se trata de un nuevo mecanismo de interacción entre factores bHLH por el que fuerza que las neuronas se desarrollen antes que el de las células ciliadas.
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Feng, Shengrui. „Lineage Tracing of Neuronal Progenitor Cells Expressing dlx1a/2a in the Zebrafish Brain“. Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31534.
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The Distal-less homeobox (Dlx) genes encode homeodomain transcription factors that play important roles in the development of limbs, sensory organs, branchial arches and the forebrain. In the forebrain, Dlx1 and Dlx2 are expressed in neuronal progenitor cells and play essential roles in GABAergic neuron differentiation and migration. In order to understand the fate of neuronal progenitor cells that express dlx1a/2a genes in the brain, we produced lines of Tg(dlx1a/2a:CreERT2) transgenic fish expressing the CreERT2 recombinase driven by regulatory elements from the dlx1a/2a locus. CreERT2 expression in these fish faithfully recapitulates that of dlx1a/2a genes in the forebrain. These fish were mated with Tg(ubi:Switch) reporter fish that express a loxP-flanked GFP gene followed by mCherry, driven by the ubiquitin promoter. Upon tamoxifen treatment, the double transgenic fish express mCherry in dlx1a/2a-expressing cells. Live imaging data showed that mCherry-expressing cells were observed first in the telencephalon and prethalamus, regions from which they migrated and populated the telencephalon, prethalamus and hypothalamus by 10dpf. Fate mapping of mCherry-expressing cells in double transgenic fish demonstrated that a majority of dlx1a/2a-expressing cells give rise to GABAergic neurons. Furthermore, as zebrafish produce new neurons throughout life, the role of dlx1a/2a during adult neurogenesis was examined. Our preliminary data showed that dlx1a/2a-expressing progenitor cells populate various domains of the forebrain during adult neurogenesis. Our lineage tracing system provides a powerful tool to investigate the origin of GABAergic neuron progenitors and the mechanisms by which they populate or repopulate the adult brain.
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Young, Fraser. „Dental pulp progenitor-derived neuronal- and oligodendrocyte-like cells for spinal cord repair“. Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/53879/.
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Spinal cord regeneration following injury represents a major clinical challenge. Over recent years, stem cells have demonstrated promise for promoting spinal repair in the lab and in early stage clinical trials through functional replacement of neuronal and glial cells and through secondary trophic mechanisms to promote endogenous regeneration. Research has primarily focused on the use of embryonic tissue-derived stem cells of potentially limited therapeutic application due to related ethical concerns. The dental pulp harbours a source of easily accessible progenitor cells that have demonstrated early promise in improving functional outcome of experimental models of spinal cord injury via growth factor release. This thesis explores the potential of dental pulp progenitor cells (DPPCs) to promote spinal repair through direct cellular replacement. Progenitor cells isolated from murine incisors were found to express early stage neural and glial markers. Specific protocols were developed demonstrating the ability of DPPCs to differentiate in vitro into neuronal-like and oligodendrocyte-like cells with appropriate morphology and expression of mature markers. Electrophysiological testing revealed that DPPC-derived neuronal-like cells were of an immature non-functional phenotype. Undifferentiated DPPCs injected into an ex vivo spinal cord slice model showed signs of proliferation, migration and spontaneous differentiation within spinal tissue. DPPCs pre-differentiated into oligodendrocyte-like cells failed to survive transplantation but neuronally pre-differentiated cells survived, showing signs of integration into endogenous neuronal pathways. In a small scale pilot study, neuronally pre-differentiated DPPCs were transplanted into a clinically relevant in vivo model of spinal cord injury. DPPCs maintained expression of neuronal markers four weeks after grafting into the injured spinal cord. Axonal projections towards grafted cells and synaptic protein expression suggested possible integration into neuronal pathways, albeit without an associated statistical functional improvement. The results presented in this thesis provide a strong case for the potential of DPPCs to facilitate functional recovery through direct cell replacement mechanisms.
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Ochi, Shohei. „Oscillatory expression of Hes1 regulates cell proliferation and neuronal differentiation in the embryonic brain“. Kyoto University, 2020. http://hdl.handle.net/2433/253484.
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Shiota, Mitsutaka. „Isolation and characterization of bone marrow-derived mesenchymal progenitor cells with myogenic and neuronal properties“. Kyoto University, 2007. http://hdl.handle.net/2433/135737.
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Geater, Charlene. „Direct programming of neural progenitors into medium spiny neurons by transcription factor transfection“. Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/68329/.
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Huntington’s disease is an autosomal dominant neurological disease caused by an elongated CAG repeat in exon 1 of the huntingtin gene. There is currently no cure and treatments are limited. The genetic mutation causes selective cell death of the medium spiny neurons which reside in the striatum of the basal ganglia. Current disease models don’t necessarily recapitulate all aspects of the human disease and so alternatives are needed. The advent of induced pluripotent stem cells (iPSC), has allowed for HD patient specific pluripotent stem cells to be derived, hence differentiation of these cells in vitro could provide a disease model for drug testing and investigation of disease pathology. Current protocols for differentiation of pluripotent stem cells into medium spiny neurons (MSNs) are often inconsistent and lead to low yields of MSNs. Directing differentiation through forced expression of transcription factors has been used to differentiate neurons from fibroblasts and pluripotent stem cells, often with increased efficiency. Utilising transcription factors vital in post-mitotic MSN development, this study has aimed to produce MSNs in vitro, by transfection of transcription factors or combinations thereof in a multicistronic plasmid into ventral forebrain neural progenitors. This study has involved the cloning and expression of 5 different transcription factors important in MSN development in iPSC-derived neural progenitors. Two of these transcription factors; NOLZ1 (ZNF503) and ISL1 were further investigated for their ability to differentiate neural progentiroes into MSNs. This study showed that transfection of ISL1 enabled differentiation of neurons to produce a higher proportion of cells resembling MSNs, characterised by co-expression of the MSN markers DARPP32 and CTIP2 and expressing FOXP1. The combination of NOLZ1 and ISL1 in transfection improved functional maturation of neurons, becoming increasingly spontaneously active and increased excitability, as well as responding to GABA and NMDA, with dopamine D1 agonist enhancement of NMDA currents.
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Samata, Bumpei. „Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1“. 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225509.
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Nobre, André Dos Santos. „Genetically modified ventral mesencephalic neuronal progenitor cells cellular and molecular characterization in vitro/ André Dos Santos Nobre“. Hannover Bibliothek der Tierärztlichen Hochschule Hannover, 2009. http://d-nb.info/1000125483/34.
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Nobre, André dos Santos [Verfasser]. „Genetically modified ventral mesencephalic neuronal progenitor cells : cellular and molecular characterization in vitro / André Dos Santos Nobre“. Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2009. http://d-nb.info/1000125483/34.
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Wang, Jinju. „Differentiation of Megakaryocytes/Platelets and Neurons from Human Endometrial Stromal Progenitor Cells“. Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1314976408.
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Goodwin, Laura Rose. „The Chromatin Remodelling Contributions of Snf2l in Cerebellar Granule Neuron Differentiation“. Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38201.
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Recent studies have uncovered de novo mutations of the gene encoding the chromatin remodelling protein Snf2l in patients with schizophrenia, Rett-like syndrome and intellectual disability. Snf2l and its closely related protein, Snf2h, play a critical role in embryonic and post-natal brain development. Murine models lacking functional Snf2h or Snf2l point to complementary activities of these remodelers; Snf2h cKO mice present with a significantly reduced cerebellum, while Snf2l Ex6DEL (exon 6 deleted) cerebella are larger than their wild-type counterparts. Granule neuron progenitors (GNPs) isolated from Ex6DEL cerebella display delayed cell cycle exit and hindered terminal differentiation compared to wild-type controls. Moreover, loss of Snf2l activity results in widespread transcriptome shifts which underlie the Ex6DEL GNP differentiation phenotype. In particular, key transcription factors are differentially expressed without Snf2l remodelling activity. We confirm that ERK pathway activation is misregulated in Ex6DEL GNPs, possibly in response to elevated fibroblast growth factor 8 (Fgf8) expression in these cultures. We find that Snf2l activity maintains the chromatin landscape throughout GNP differentiation, as Ex6DEL cultures have a global increase in chromatin accessibility. We suggest that Snf2l-mediated chromatin condensation is responsible for proper regulation of gene expression programs in GNP differentiation.
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Li, Yue, und 李越. „Caveolin-1 is a negative regulator of neuronal differentiation of neural progenitor cells in vitro and in vivo“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46918863.
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Chwastek, Damian. „Elucidating the Contribution of Stroke-Induced Changes to Neural Stem and Progenitor Cells Associated with a Neuronal Fate“. Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41839.
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Following stroke there is a robust increase in the proliferation of neural stem and progenitor cells (NSPCs) that ectopically migrate from the subventricular zone (SVZ) to surround the site of damage induced by stroke (infarct). Previous in vivo studies by our lab and others have shown that a majority of migrating NSPCs when labelled prior to stroke become astrocytes surrounding the infarct. In contrast, our lab has shown that the majority of NSPCs when labelled after stroke become neurons surrounding the infarct. This thesis aims to elucidate the contributions of intrinsic changes that can alter the temporal fate of the NSPCs. The NSPCs were fate mapped in this study using the nestin-CreERT2 mouse model and strokes were induced using the photothrombosis model within the cortex. In alignment with our previous findings, fate-mapping the NSPCs using a single injection of tamoxifen treatment revealed a temporal-specific switch in neuronal fate when NSPCs were labeled at timepoints greater than 7 days following stroke. Single cell RNA sequencing and histological analysis identified significant differences in the proportion of populations of NSPCs and their progeny labeled at the SVZ in the absence or presence of a stroke. NSPCs labelled after stroke were comprised of a reduced proportion of quiescent neural stem cells alongside an accompanied increase in doublecortin-expressing neuroblasts. The RNA transcriptional profile of the NSPCs labelled also revealed NSPCs and their progeny labeled after stroke had an overall enrichment for a neuronal transcription profile in all of the labeled cells with a reduction in astrocytic gene expression in quiescent and activated neural stem cells. Furthermore, we highlight the presence of perturbed transcriptional dynamics of neuronal genes, such as doublecortin following stroke. Altogether, our study reveals following a stroke there is a sustained intrinsic regulated neuronal-fated response in the NSPCs that reside in the SVZ that may not be exclusive from extrinsic regulation. This work raises the challenge to learn how to harness the potential of this response to improve recovery following stroke through examining their contributions to recovery.
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Buscarlet, Manuel. „The neural progenitor to neuron transition : role and regulation of GrouchoTLE proteins“. Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115670.
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Groucho/transducin-like Enhancer of split (Gro/TLE) family proteins are corepressors found as part of multiple transcriptional complexes that play significant roles during many developmental processes, including neurogenesis. This thesis sought to characterize the molecular mechanisms underlying the biological activity of Gro/TLE1. More specifically, the aim was to clarify the contribution of different transcriptional cofactors, as well as phosphorylation events induced by cofactor binding, to Gro/TLE1 ability to inhibit neuronal differentiation from proliferating neural progenitor cells.By characterizing specific point mutations within the C-terminal domain of Gro/TLE1, we were able to selectively impair binding of Gro/TLE1 to different classes of DNA-binding proteins and then assess the effect of those mutations on Gro/TLE1 anti-neurogenic function. These studies showed that the inhibition of cerebral cortex (cortical) neuron differentiation by Gro/TLE1 requires interaction with transcription factors that use short tetrapeptide sequences, WRP(W/Y), to recruit Gro/TLE1. In contrast, interactions with proteins that either interact with the C-terminal domain of Gro/TLE1 using a different type of binding sequence, termed engrailed homology 1 (Eh1) motif, or bind to the N-terminal part of the protein, are not required for Gro/TLE1 anti-neurogenic function.
Using a similar strategy based on mutation analysis, we characterized point mutations that block the hyperphosphorylation of Gro/TLE1 induced by transcription cofactor binding ("cofactor-activated phosphorylation") without impairing cofactor binding and transcriptional corepression ability. These mutations map at phosphorylatable serine residues, Ser-286, Ser-289, and Ser298. Mutation of those residues to alanine blocks/reduces both cofactor-activated phosphorylation and anti-neurogenic activity of Gro/TLE1, demonstrating that cofactor-activated phosphorylation is required for that function. Tandem mass spectroscopy analysis showed further that Ser-286 is phosphorylated. Taken together, these findings characterize the role of cofactor-activated phosphorylation and identify residues important for this mechanism.
Our studies also showed that homeodomain-interacting protein kinase 2 (HIPK2) mediates phosphorylation of Gro/TLE1 when the latter is complexed with transcriptional partners of the WRP(W/Y) motif family. However, HIPK2 is not involved in Gro/TLE1 cofactor-activated phosphorylation. Rather, HIPK2--mediated phosphorylation is antagonistic to the latter and decreases the ability of Gro/TLE1 to interact and repress transcription with WRP(W/Y) motif proteins.
Taken together, these results improve significantly our understanding of the mechanisms underlying the anti-neurogenic function of Gro/TLE1. This information provides new insight into the regulation of mammalian neuronal development and, possibly, other developmental processes controlled by Gro/TLE proteins.
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Bou-Rouphaël, Johnny. „A new role for Barhl1 in a cerebellar germinative zone as inhibitor of T-cell factors transcriptional activity“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS009.
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Le cervelet humain contient plus de 50 % des neurones cérébraux. Les neurones granulaires cérébelleux représentent la population neuronale majeure. Les progéniteurs des neurones granulaires (GNP), définis par l’expression de Atoh1, émergent à partir de la lèvre rhombique supérieure (URL), une zone germinative située dans le territoire cérébelleux. Au cours du développement, les GNP prolifèrent, migrent et se différencient. Chacun de ces processus est régulé par un certain nombre de facteurs de transcription et de voies de signalisation. Les « T-Cell Factors » (Tcf/Lef) » sont des effecteurs transcriptionnels agissant en aval de la signalisation Wnt/β-caténine. Bien que les Tcf soient transcriptionnellement actifs dans la URL, leur(s) fonction(s) et leur(s) régulateur(s) développementaux n'ont été étudié. Le facteur de transcription « BarH-like 1 » (Barhl1) est exprimé dans les GNPs engagés, situés dans des zones dépourvues d'une activité transcriptionnelle Tcf. Par conséquent, les objectifs de cette thèse étaient d'étudier les fonctions de Tcf et Barhl1 en tant que régulateurs du développement des GNPs chez le Xénope. Les données présentées dans cette thèse englobent une analyse approfondie des marqueurs majeurs impliqués dans le développement des GNPs chez les amphibiens, et une étude des fonctions de Barhl1 et Tcf dans ce processus développemental. Nos expériences de gain et de perte de fonction, ainsi que l'analyse transcriptomique en absence de Barhl1 dans le rhombomère 1 valident un rôle clé de Tcf en tant qu'activateur transcriptionnel de atoh1 et en tant qu'inducteur du territoire cérébelleux, et un rôle pour Barhl1 en tant qu'inhibiteur développemental de l’activité Tcf, permettant aux GNPs de sortir de l'URL. Nous avons identifié des gènes cibles clés inhibés par Barhl1, et impliqués dans le maintien d’une zone germinativeThe human cerebellum hosts more than 50% of all brain neurons. Cerebellar granule neurons are the smallest and most abundant neurons. atonal homologue 1 (Atoh1)-expressing granule neuron progenitors (GNPs) emerge from the upper rhombic lip (URL), a germinative zone located in the cerebellar primordium and displaying features of a niche of neural stem cells. GNPs proliferate, migrate, and differentiate to settle into the internal granule layer. These processes are tightly regulated by a number of transcription factors and signaling pathways. T-Cell Factor/Lymphoid Enhancer-binding Factor (Tcf/Lef) are transcriptional effectors acting downstream of Wnt/β-catenin signaling. Although Tcf is transcriptionally active in the URL, neither its function(s) nor its developmental regulator(s) have been addressed in this area. The transcription factor BarH-like 1 (Barhl1) is expressed in committed GNPs located in areas devoid of Tcf transcriptional activity. The aims of this thesis were to investigate the functions of Tcf and of Barhl1 as regulators of GNPs development using amphibian as experimental model. The data presented in this work encompass a thorough analysis of the spatial and temporal expressions of key markers involved in GNP development in amphibian, and an investigation of Barhl1 and Tcf functions in this developmental process. Our gain and loss of function experiments, together with the transcriptomic analysis of Barhl1 depletion in the rhombomere 1 validate a key role for Tcf as a transcriptional activator of atoh1 and as an inducer of the URL territory, and for Barhl1 as a developmental inhibitor of Tcf activity allowing GNPs to exit the URL. We identified key genes inhibited by Barhl1 and involved in the maintenance of URL germinative zone
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Weeranantanapan, Oratai. „The role of L1-CNTNs in controlling SHH-induced proliferation of cerebellar granule neuron progenitors“. Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/6180/.
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Najas, Sales Sònia 1985. „Role of DYRK1A in the development of the cerebral cortex : Implication in Down Syndrome“. Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/380895.
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In this work we have assessed the possible contribution of the human chromosome-21 gene DYRK1A in the developmental cortical alterations associated with Down Syndrome using the mBACTgDyrk1a mouse, which carries 3 copies of Dyrk1a, and a trisomic model of the syndrome, the Ts65Dn mouse. We show that trisomy of Dyrk1a changes the cell cycle parameters of dorsal telencephalic radial glial (RG) progenitors and the division mode of these progenitors leading to a deficit in glutamatergic neurons that persist until the adulthood. We demonstrate that Dyrk1a is the triplicated gene that causes the deficit in early-born cortical glutamatergic neurons in Ts65Dn mice. Moreover, we provide evidences indicating that DYRK1A-mediated degradation of Cyclin D1 is the underlying mechanism of the cell cycle defects in both, mBACTgDyrk1a and Ts65Dn dorsal RG progenitors. Finally, we show that early neurogenesis is enhanced in the medial ganglionic eminence of mBACTgDyrk1a embryos resulting in an altered proportion of particular cortical GABAergic neuron types. These results indicate that the overexpression of DYRK1A contributes significantly to the formation of the cortical circuitry in Down syndrome.En aquest treball s'ha avaluat la possible contribució del gen DYRK1A, localitzat en el cromosoma humà 21, en les alteracions del desenvolupament de l’escorça cerebral associades a la Síndrome de down (SD) mitjançant l’estudi de dos models murins: el ratolí mBACTgDyrk1a, el qual conté 3 còpies de Dyrk1a, i el ratolí Ts65Dn, un dels models trisòmics de la SD més ben caracteritzats. Els nostres resultats mostren que la trisomia de Dyrk1A altera alguns paràmetres del cicle cel•lular i el tipus de divisió dels progenitors neurals del telencèfal dorsal, donant lloc a un dèficit de neurones glutamatèrgiques que persisteix fins l’edat adulta. Hem demostrat que Dyrk1a és el gen triplicat responsable del dèficit inicial en la generació de neurones glutamatèrgiques corticals observat en el ratolí Ts65Dn. A més a més, hem proporcionat evidències de que la degradació de Ciclina D1 induïda per DYRK1A és el mecanisme molecular subjacent a les alteracions de cicle cel•lular observades en els progenitors neuronals dels embrions mBACTgDyrk1a i Ts65Dn. Per altra banda, hem demostrat que la neurogènesis inicial està incrementada en l’eminència ganglionar medial dels embrions mBACTgDyrk1a, fet que altera la proporció de subtipus específics d’interneurones GABAèrgiques en l’escorça cerebral adulta. En conclusió, els nostres resultats indiquen que la sobreexpressió de DYRK1A contribueix significativament a la formació dels circuits cortical en la SD.
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SALEM, RITA. „Adult hippocampal neural progenitor cells: an Important In vitro tool for studying complex mechanisms regulating adult neurogenesis“. Doctoral thesis, Università del Piemonte Orientale, 2017. http://hdl.handle.net/11579/86925.
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Adult hippocampal neurogenesis (ahNG) is a peculiar form of neural plasticity involved in crucial brain functions including cognition, mood and stress response. Adult hippocampal neural progenitor cells (ahNPC) differentiation is modulated positively or negatively by several factors. Understanding the mechanisms regulating ahNG will shed light on its role in brain physiopathology. Astrocytes, one of the major component of the neurogenic niche, might regulate ahNPC fate specification. Little is known about the identity of astrocytes-secreted proteins and the subcellular mechanisms mediating their modulatory effect. Interestingly ahNG is deregulated in neuropsychiatric disorders such as major depression. The specific involvement of serotonin (5-HT) receptors family in mediating antidepressants (AD) effect add more complication into serotonin role in depression and is still not extensively described. Several studies documented a role of NF-B signaling in ahNPC response to proneurogenic molecules. Yet scarce data described how the knockout of NF-B p50 subunit (p50KO) could affect ahNG. In vitro analysis of astrocytes conditioned media (ACM) effect on ahNPC differentiation, showed that p50 absence induced intrinsic and extrinsic defects in both cell types. These results could explain earlier study published in our group showing that p50KO mice have reduced ahNG and severe deficits in hippocampal-dependent cognitive performance. Moreover, lipocalin-2 (LCN-2) was identified as a novel astrocyte-derived proneurogenic signal. In the second part of the study we showed that 5-HT2A/2C receptors antagonism and 5-HT7 activation are proneurogenic on ahNPC. Moreover NF-B p50 subunit presence was required for the multimodal AD induced increase of neurogenesis. In conclusion, ahNPC modulation by astrocyte-released factors and serotonin receptors might be future pharmacological targets for increasing ahNG specifically in neurodegenerative and neuropsychiatric disorders.
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Hamze, Carmen. „Mitofusin 1 and Mitofusin 2 Function in the Context of Brain Development“. Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20347.
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Mitofusin 1 and 2 are outer-mitochondrial membrane proteins that have been shown to be involved in fusion. Mitofusin 2 has also been associated with apoptosis and development. When Mfn1 and Mfn2 were each conditionally knocked out from the cerebellum, Purkinje cells in Mfn2 deficient cerebellum during development had undergone neurodegeneration. Mutations in Mfn2 have also been associated with the Charcot Marie Tooth Type 2A (CMT2A). We want to asses the effect Mfn2 and Mfn1 might have on the development of other regions of the brain such as the telencephalon. We generated Mfn1 and Mfn2 conditional knockouts in the telencephalon by crossing them with Foxg1 Cre - a cre expressed in the telencephalon. We found that Mfn1 deficient mice have lost their corpus callosum at the midline, but survive over 6 months with a decrease in progenitor cells postnatally. Mfn2 deficient mice die between P9 and P12 with a decrease in progenitor cells postnatally and a decrease in number of neurons in the cortex. Therefore, our results suggest that Mfn1 and Mfn2 play a significant role in the development of the telencephalon.
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Yerrapragada, Sri Meghana. „The Protective Effects of miR-210 Modified Endothelial Progenitor Cells Released Exosomes in Hypoxia/Reoxygenation Injured Neurons“. Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1629835915811575.
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Fish, Jennifer. „The evolution of neuronal progenitor cell division in mammals: The role of the abnormal spindle-like microcephaly associated (Aspm) protein and epithelial cell polarity“. Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2007. http://nbn-resolving.de/urn:nbn:de:swb:14-1184837029919-80275.
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Among mammals, primates are exceptional for their large brain size relative to body size. Relative brain size, or encephalization, is particularly striking among humans and their direct ancestors. Since the human-chimp split 5 to 7 million years ago, brain size has tripled in the human lineage (Wood & Collard 1999). The focus of this doctoral work is to investigate some of the cell biological mechanisms responsible for this increase in relative brain size. In particular, the processes that regulate symmetric cell division (ultimately generating more progenitors), the constraints on progenitor proliferation, and how neural progenitors have overcome these constraints in the process of primate encephalization are the primary questions of interest. Both functionally analyses in the mouse model system and comparative neurobiology of rodents and primates are used here to address these questions. Using the mouse model system, the cell biological role of the Aspm (abnormal spindle-like microcephaly associated) protein in regulating brain size was investigated. Specifically, Aspm function in symmetric, proliferative divisions of neuroepithelial (NE) cells was analyzed. It was found that Aspm expression in the mouse neuroepithelium correlates in time and space with symmetric, proliferating divisions. The Aspm protein localizes to NE cell spindle poles during all phases of mitosis, and is down-regulated in cells that undergo asymmetric (neurogenic) cell divisions. Aspm RNAi alters the division plane in NE cells, increasing the likelihood of premature asymmetric division resulting in an increase in non-NE progeny. At least some of the non-NE progeny generated by Aspm RNAi migrate to the neuronal layer and express neuronal markers. Importantly, whatever the fate of the non-NE progeny, their generation comes at the expense of the expansion of the proliferative pool of NE progenitor cells. These data have contributed to the generation of an hypothesis regarding evolutionary changes in the regulation of spindle orientation in vertebrate and mammalian neural progenitors and their impact on brain size. Specifically, in contrast to invertebrates that regulate the switch from symmetric to asymmetric division through a rotation of the spindle (horizontal versus vertical cleavage), asymmetric NE cell division in vertebrates is accomplished by only a slight deviation in the cleavage plane away from the vertical, apical-basal axis. The requirement for the precise alignment of the spindle along the apical-basal axis in symmetric cell divisions may have contributed to selection on spindle “precision” proteins, thus increasing the number of symmetric NE cell division, and contributing to brain size increases during mammalian evolution. Previous comparative neurobiological analyses have revealed an increase in basally dividing NE cells in the brain regions of highest proliferation and in species with the largest brains (Smart 1972a,b; Martinez-Cerdeno et al. 2006). The cell biological characteristics of these basally dividing cells are still largely unknown. We found that primate basal progenitors, similar to rodent apical progenitors, are Pax6+. This suggests that primate basal progenitors may share other properties with rodent apical progenitors, such as maintenance of apical contact. Our previous finding that artificial alteration of cleavage plane in NE cells affects their ability to continue proliferating supports the hypothesis that the apical membrane and junctional complexes are cell fate determinants (Huttner & Kosodo 2005). As such, the need to maintain apical membrane contact appears to be a constraint on proliferation (Smart 1972a,b; Smart et al. 2002). Together, these data favor the hypothesis that primate basally dividing cells maintain apical contact and are epithelial in nature.
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Chen, Kesi, Yasushi Ohkubo, Dana Shin, Thomas Doetschman, L. P. Sanford, Hongqi Li und Flora Vaccarino. „Decrease in excitatory neurons, astrocytes and proliferating progenitors in the cerebral cortex of mice lacking exon 3 from the Fgf2 gene“. BioMed Central, 2008. http://hdl.handle.net/10150/610071.
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BACKGROUND:The Fgf2 gene is expressed in the brain neuroepithelium during embryonic development and in astroglial cells throughout life. Previous knockout studies suggested that FGF2 plays a role in the proliferation of neural progenitors in the embryonic cerebral cortex. These studies exclusively used knockout alleles lacking the Fgf2 exon 1. However, the description of putative alternative exons located downstream from the canonical exon 1 raised the possibility that alternatively spliced transcripts may compensate for the lack of the canonical exon 1 in the Fgf2 -/- mice.RESULTS:We generated and characterized a new line of Fgf2 knockout mice lacking the expression of exon 3, which is conserved in all Fgf2 transcripts and contains essential heparin and receptor binding interfaces. The expression of Fgf2 exon 3 was prevented by inserting a transcriptional STOP cassette in the Fgf2 genomic locus. These mice demonstrate a phenotype in the adult neocortex characterized by decreased density and number of cortical excitatory neurons and astrocytes, which is virtually identical to that of the Fgf2 -/- mice lacking exon 1. In addition, we also show that the Fgf2 exon 3 knockout mice have decreased proliferation of precursors in the adult cerebral cortex, which had not been previously investigated in the other mutant lines.CONCLUSION:The results demonstrate that the phenotype of two completely different Fgf2 KO mouse lines, lacking exon 1 or exon 3, is remarkably similar. The combined results from these KO models clearly indicate that FGF2 plays a role in cortical cell genesis during embryonic development as well as in adulthood. Thus, FGF2 may be required for the maintenance of the pool of adult cortical progenitor cells.
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McCabe, Kathryn Leigh. „The transition from progenitor cell to neuron : fibroblast growth factors and their role in retinal ganglion cell neurogenesis /“. Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/10640.
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Larsson, Jimmy. „Neural stem and progenitor cells cellular responses to known and novel factors /“. Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110722.
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McLean, Will (Will James). „Defined populations of inner ear progenitor cells show limited and distinct capacities for differentiation into hair cells, neurons, and glia“. Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/97320.
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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 66-74).
Despite the fact that mammalian hair cells and neurons do not naturally regenerate in vivo, progenitor cells exist within the postnatal inner ear that can be manipulated to generate hair cells and neurons. This work reveals the differentiation capabilities of distinct inner ear progenitor populations and pinpoints cell types that can become cochlear hair cells, vestibular hair cells, neurons, and CNS glia. We expanded and differentiated cochlear and vestibular progenitors from mice (postnatal days 1-3) and analyzed the cells for expression of mature properties by RT-PCR, immunostaining, and patch clamping. Whereas previous reports suggested that inner ear stem cells may be pluripotent and/or revert to a more neural stem cell fate, we find that cells from each organ type differentiated into cells with characteristics of the respective organ. Only cochlear-derived cells expressed the outer-hair-cell protein, prestin, while only vestibular derived cells expressed the vestibular extracellular matrix marker, otopetrin. Since Atohi expression is consistently found in new hair cells, we used an Atohl-nGFP mouse line to identify hair cell candidates. We find that cells expressing Atohl also expressed key transduction, hair bundle, and synaptic genes needed for proper function. Whole-cell patch clamp recordings showed that Atoh1-nGFP+ cells derived from both cochlear and vestibular tissue had voltage gated ion channels that were typical of postnatal hair cells. Only vestibular-derived AtohinGFP+ cells, however, had Ih, a hyperpolarization-activated current typical of native vestibular hair cells but not native cochlear hair cells. Lineage tracing studies with known supporting cell and glial cell markers showed that progenitor capacity of cochlear supporting cells positive for Lgr5 (Lgr5+ cells) was limited to differentiation into hair cell-like cells but not neuron-like cells. In contrast, glial cells positive for PLP (PLP1+ cells) from the auditory nerve differentiated into multiple cell types, with properties of neurons, astrocytes, or mature oligodendrocytes but not hair cells. Thus, PLP+ progenitor cells within the auditory nerve are limited to neuronal or glial fates but have greater potency than Lgr5+ progenitors, which only formed hair cell-like cells. In summary, this work identifies distinct populations of post-natal inner ear progenitors and delineates their capacity for differentiation and maturation.
by Will McLean.
Ph. D.
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Yulius, Hermanto. „Transplantation of feeder-free human induced pluripotent stem cell-derived cortical neuron progenitors in adult male Wistar rats with focal brain ischemia“. Kyoto University, 2019. http://hdl.handle.net/2433/242389.
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Poirier, Véronique. „Manipulation expérimentale des progéniteurs neuronaux de la crête neurale de mammifère“. Cachan, Ecole normale supérieure, 1994. http://www.theses.fr/1994DENS0011.
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Il a été mis au point un modèle in vitro qui reproduit les interactions in vivo des cellules de crête neurale de souris avec leur environnement de migration. Ce modèle a permis: 1) de démontrer que les somites libèrent des facteurs diffusibles qui induisent la différenciation sympatho-adrénergique des cellules de crête neurale. Ces facteurs diffusibles ont un poids moléculaire compris entre 25 et 50 kd, sont affines pour l'héparine et sont responsables de l'engagement des progéniteurs neuronaux dans le lignage sympatho-adrénergique durant les deux premiers jours de culture correspondant aux dixième et onzième jours du développement embryonnaire; 2) de mettre en évidence que les facteurs diffusibles induisent une hétérogénéité des dérivés neuronaux. Nous avons montre que ces dérivés neuronaux sont issus de deux progéniteurs neurogéniques distincts: un progéniteur engage et un progéniteur bipotentiel, sensible a l'acide rétinoïque libéré par le tube neural et aux facteurs diffusibles libérés par les somites. Acide rétinoïque et facteurs diffusibles modulent la contribution relative des progéniteurs neurogéniques dans les différents lignages neuronaux, permettant ainsi la mise en place de la diversité phénotypique qui caractérise le système nerveux des vertèbres; 3) de manipuler expérimentalement les mécanismes d'adhésion impliques dans la différenciation neuronale et ainsi de montrer qu'il existe une hiérarchie des molécules d'adhésion utilisées au cours du développement
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Serre, Angéline. „STRATEGIES D'OMOGENEISATION DES POPULATIONS DE PROGENITEURS NERVEUX FOETAUX HUMAINS DANS UNE PERSPECTIVE DE THERAPIE CELLULAIRE DU SYSTEME NERVEUX CENTRAL“. Phd thesis, Université Pierre et Marie Curie - Paris VI, 2007. http://tel.archives-ouvertes.fr/tel-00184239.
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Dans une perspective de médecine régénératrice, les cellules souches nerveuses et progénitrices fœtales humaines constituent indéniablement un des outils les plus adaptés au traitement des lésions du SNC et des maladies neurodégénératives. Jusqu'à présent, leur utilisation en thérapie cellulaire a eu recours à des populations hétérogènes composées à la fois de cellules immatures, de cellules en voie de différenciation et de cellules pleinement différenciées. Or des études récentes ont révélé l'intérêt de disposer de populations enrichies en un type cellulaire donné afin d'améliorer l'efficacité des greffes. Pour homogénéiser les populations et mieux cibler les pathologies, nous avons donc mis en œuvre deux stratégies. La première consiste à surexprimer, dans les cellules en culture, les gènes proneuraux à motif bHLH Ngn1, Ngn2, Ngn3 et Mash1 au travers de vecteurs lentiviraux dits « de différenciation ». Cette surexpression a permis d'orienter la différenciation des cellules majoritairement vers le lignage neuronal et également de spécifier des sous-types neuronaux. La seconde méthode utilise des vecteurs lentiviraux traceurs pour exprimer une protéine rapportrice sous le contrôle de promoteurs spécifiques des différents lignages du SNC en vue de leur sélection par tri cellulaire. Nous avons ainsi utilisé le promoteur Nestine pour les cellules immatures, le promoteur Synapsine pour les cellules neuronales et le promoteur GFAP pour les cellules astrocytaires. Si les promoteurs Synapsine et GFAP ont révélé une spécificité contestable, le promoteur Nestine, quant à lui, a permis de sélectionner une population enrichie à 81% en cellules nestine+. Ce travail s'inscrit dans un projet de plus grande envergure, qui a pour but d'évaluer les bénéfices de greffes de ces populations homogénéisées.
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Lehmann, Nathalie. „Development of bioinformatics tools for single-cell transcriptomics applied to the search for signatures of symmetric versus asymmetric division mode in neural progenitors“. Electronic Thesis or Diss., Université Paris sciences et lettres, 2021. http://www.theses.fr/2021UPSLE070.
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Ces dernières années, l’émergence des approches en cellules uniques (scRNA-seq) a favorisé la caractérisation de l’hétérogénéité cellulaire avec une précision inégalée. Malgré leur démocratisation, l’analyse de ces données reste complexe, en particulier pour les organismes dont les annotations sont incomplètes. Au cours ma thèse, j’ai observé que les annotations génomiques du poulet sont lacunaires, ce qui engendre la perte d’un grand nombre de lectures de séquençage. J’ai évalué à quel point une annotation améliorée affecte les résultats biologiques et les conclusions issues de ces analyses. Nous proposons une nouvelle approche basée sur la ré-annotation du génome à partir de données scRNA-seq et de RNA-seq bulk en lectures longues. Ce projet de biologie computationnelle s’appuie sur une étroite collaboration avec l’équipe expérimentale de Xavier Morin (IBENS). Le principal objectif biologique est la recherche de signatures de mode de division symétrique et asymétrique au sein de progéniteurs neuronaux. Afin d’identifier les principaux changements transcriptionnels, j’ai mis en place des approches dédiées à la recherche de signatures géniques à partir de données scRNA-seqIn recent years, single-cell RNA-seq (scRNA-seq) has fostered the characterization of cell heterogeneity at a remarkable high resolution. Despite their democratization, the analysis of scRNA-seq remains a challenge, particularly for organisms whose genomic annotations are partial. During my PhD, I observed that the chick genomic annotations are often incomplete, thus resulting in a loss of a large number of sequencing reads. I investigated how an enriched annotation affects the biological results and conclusions from these analyses. We developed a novel approach based on the re-annotation of the genome with scRNA-seq data and long reads bulk RNA-seq. This computational biology project capitalises on a tight collaboration with the experimental team of Xavier Morin (IBENS). The main biological focus is the search for signatures of symmetric versus asymmetric division mode in neural progenitors. In order to identify the key transcriptional switches that occur during the neurogenic transition, I have implemented bioanalysis approaches dedicated to the search for gene signatures from scRNA-seq data
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MARCUZZO, STEFANIA. „New insights in the understanding of motor neuron disease by longitudinal brain and muscle MRI analysis and characterization of spinal cord-derived stem cells in G93-SOD1 mouse model of ALS“. Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/43854.
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Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disorder caused by the degeneration of motor neurons in the CNS, which results in complete paralysis of skeletal muscles. To establish the timeframe of motor neuron degeneration in relation to muscle atrophy in motor neuron disease, we have used MRI to monitor changes throughout disease in brain and skeletal muscle of G93A-SOD1 mice, a purported model of ALS. Longitudinal MRI examination of the same animals indicated that muscle volume in the G93A-SOD1 mice was significantly reduced from as early as week 8 of life, four weeks prior to clinical onset. Progressive muscle atrophy from week 8 onwards was confirmed by histological analysis. In contrast, brain MRI indicated that neurodegeneration occurs later in G93A-SOD1 mice, with hyperintensity MRI signals detected only at weeks 10-18. Neurodegenerative changes were observed only in the motor nuclei areas of the brainstem; MRI changes indicative of neurodegeneration were not detected in the motorcortex where first motor neurons originate, even at the late disease stage. This longitudinal MRI study establishes unequivocally that, in the experimental murine model of ALS, muscle degeneration occurs before any evidence of neurodegeneration and clinical signs, supporting the postulate that motor neuron disease can initiate from muscle damage and result from retrograde dying-back of the motor neurons.
In G93A-SOD1 ALS mice the response to neurodegeneration comprises proliferation and migration of ependymal stem progenitor cells (epSPCs), normally present and quiescent in spinal cord. We isolated epSPCs from G93A-SOD1 mice at 8 (asymptomatic) and 18 (symptomatic) weeks of age, and characterized the ability of epSPC cultures to proliferate and differentiate into the three neural cell lineages. G93A epSPCs produced neurospheres of self-renewing cells, and differentiated into more neurons and fewer astrocytes than control epSPCs, whereas oligodendrocytes did not show difference between the examined groups. The G93A-SOD1 neurons were small and the astrocytes were consistently activated. MicroRNA analysis revealed that miR-9 and miR-124a, involved in neural cell fate, were upregulated in differentiating G93A-SOD1 epSPCs, particularly at 18 weeks. miR-19a and miR-19b, implicated in cell-cycle regulation, were differentially expressed during epSPC differentiation in G93A-SOD1 compared with controls. Our findings demonstrated that G93A-SOD1 epSPCs have neurogenic potential constituting a source of multipotent cells useful for understanding the ALS pathogenesis and for identifying new therapeutic targets.
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Kalve, Ieva [Verfasser]. „The co-layer method as an efficient way for neurotrophic factor release by transplanted genetically modified neuronal progenitor cells in a rat model of Parkinson's disease : Analysis of morphological and functional integration / Ieva Kalve“. Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/1046715712/34.
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Fares, Mazigh. „Modélisation pathologique de l'infection par le virus de l'encéphalite à tiques et réponse antivirale induite dans les neurones et astrocytes dérivées de progéniteurs neuraux foetaux humains“. Thesis, Paris, Institut agronomique, vétérinaire et forestier de France, 2018. http://www.theses.fr/2018IAVF0025.
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Le virus de l’encéphalite à tiques (TBEV), membre de la famille des Flaviviridae et du genre Flavivirus, est d’un point de vue médical, l’arbovirus plus important en Europe et en Asie du Nord-Est. Il est responsable de symptômes fébriles et de manifestations neurologiques allant de la méningite légère à l'’encéphalomyélite sévère pouvant être fatale. En dépit de son importance médicale, la neuropathogenèse induite par TBEV reste peu caractérisée. Ici, nous avons utilisé des cellules neurales humaines différenciées à partir de progéniteurs neuraux fœtaux pour modéliser l’infection in vitro et élucider les mécanismes par lesquels le virus endommage le cerveau humain. Nos résultats ont montré que les neurones et les cellules gliales (astrocytes et oligodendrocytes) étaient permissifs au TBEV. Les neurones étaient massivement infectés et la cible d’un effet cytopathique important (perte de 60 % des neurones 7 jours après l’infection). Les astrocytes étaient également infectés, bien qu’à des niveaux inférieurs, et l’infection avait un effet modéré sur leur survie (perte de 30 % des astrocytes 7 jours après l’infection), induisant une hypertrophie caractéristique d’une astrogliose. Ainsi, deux événements majeurs décrits dans les cerveaux de patients infectés par TBEV (perte neuronale et astrogliose) étaient reproduits dans ce modèle cellulaire in vitro, démontrant ainsi sa pertinence pour des études de neuropathogenèse. Nous l’avons donc utilisé pour étudier la réponse antivirale induite par TBEV. En utilisant des PCR arrays, nous avons d’abord montré que le virus induisait une forte réponse antivirale caractérisée par une surexpression de senseurs viraux, de cytokines et de gènes stimulés par l’interféron. Puis, en établissant des cultures enrichies en neurones humains et astrocytes humains, nous avons montré que ces deux types cellulaires participaient à la réponse antivirale globale. Cependant, les astrocytes élaboraient une réponse antivirale plus forte que les neurones. Ces résultats, en démontrant que les neurones humains et les astrocytes humains élaborent chacun une réponse antivirale unique suite à l’infection, suggèrent que leur susceptibilité particulière à TBEV serait due à leur différente capacité à établir une réponse antivirale protectriceTick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, genus Flavivirus, is, from a medical point of view, the most important arbovirus in Europe and North-East Asia. It is responsible for febrile illness and, in some cases, for neurological manifestations ranging from mild meningitis to severe encephalomyelitis that can be fatal. Despite its medical importance, TBEV-induced neuropathogenesis remains poorly understood. Here, we used human neural cells differentiated from fetal neural progenitor cells (hNPCs) to model the infection in vitro and to decipher the mechanisms by which the virus damages the human brain. Our results showed that neurons and glial cells, namely astrocytes and oligodendrocytes, were permissive to TBEV. Neurons were massively infected and subjected to a dramatic cytopathic effect (60% loss 7 days post-infection). Astrocytes were also infected, although at lower levels, and the infection had a moderate effect on their survival (30% loss 7 days post infection), inducing a hypertrophied morphology characteristic of astrogliosis. Thus, two major cellular events described in TBEV-infected human brain (i.e. neuronal loss and astrogliosis) were reproduced in this in vitro cellular model, showing its relevance to study TBEV-induced neuropathogenesis. We therefore used it to tackle TBEV induced antiviral response. Using PCR arrays, we first showed that TBEV induced a strong antiviral response characterized by the overexpression of viral sensors, cytokines and interferon-stimulated genes (ISGs). Then, setting up enriched cultures of human neurons and human astrocytes, we further showed that the two cellular types were participating in the global antiviral response. However, astrocytes developed a stronger antiviral response than neurons. These results, by demonstrating that human neurons and human astrocytes have unique antiviral potential, suggest that their particular susceptibility to TBEV infection is due to their different capacity to mount a protective antiviral response
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BACIGALUPPI, SUSANNA. „Ruolo e potenziale delle cellule progenitrici endoteliali nel vasospamo cerebrale“. Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/27113.
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Title: Role and potential of endothelial progenitor cells in cerebral vasospasm Abstract: Background and aim:
Despite many treatment approaches, cerebral vasospasm and delayed ischemic neuronal damage (DIND) still represent a serious threat to patients with subarachnoid haemorrhage (SAH). Endothelial progenitor cells (EPC) have been involved as prognostic indicators in several vascular diseases and mesenchymal stem cells already have shown some benefits in ischemic injury.
Aim of this study was to investigate the therapeutic potential of endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) in attenuating or preventing vasospasm and DIND in patients with SAH.
Methods:
Given the emergent role of DIND as a result of multifactorial hypoperfusion stress in the outcome of SAH patients, the efficacy of EPC and MSC in reducing neuronal damage has been evaluated in an in vitro model of ischemia, namely the oxygen glucose deprivation (OGD), on primary rat cortical neuronal cultures.
Further, we tested in a clinical observational study SAH patients with and without vasospasm for different recruitment patterns of circulating EPC. To this purpose arterial blood samples were collected at various timepoints from admission to discharge of the patients. On these samples real-time quantitative PCR (RT-qPCR) was performed to detect gene expression relative to EPCs, since cytofluorimetric analysis appeared not sensitive enough to detect this rare cell population.
Results:
Though present results need further confirmation, in vitro it was observed that both MSC and EPC treatment through conditioned medium or co-culture in transwell- although with some differences - mediate a survival advantage for OGD stressed neurons. Furthermore stem cell mediated treatment showed efficacy even when applied 24 hours after OGD stress induction.
RT-qPCR results from a small sample of SAH patients might indicate an early mobilization of EPC related gene expression in subjects that do not develop vasospasm with a peak around day 4, whereas the expression of these genes remain invariably low in patients that develop vasospasm as in controls not affected by SAH.
Conclusions:
MSCs and EPCs seem to have an important potential role in preventing DIND in vitro as well as EPC recruitment might associate with lack of vasospasm in SAH patients.
Further studies are needed to confirm these results and to prove a causal relationship between EPCs and vasospasm protection.
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Loulier, Karine. „Etude de la voie de signalisation Sonic Hedgehog et du contrôle de la prolifération cellulaire dans le cerveau mature de rongeurs“. Phd thesis, Université Paris Sud - Paris XI, 2005. http://tel.archives-ouvertes.fr/tel-00429497.
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La voie de signalisation du morphogène Sonic Hedgehog (Shh) met en jeu des processus complexes étudiés, jusque là principalement, au cours du développement embryonnaire, où Shh est primordial pour le développement du tissu nerveux. Shh transmet son action via le complexe-récepteur Patched/Smoothened (Ptc/Smo) et le facteur de transcription Gli1, et interagit avec la glycoprotéine Hip (Hedgehog interacting protein) proposée comme antagoniste des protéines Hedgehog. Des analyses biochimiques ont permis de montrer qu'en plus de la forme membranaire, une forme soluble de Hip existe, notamment dans le cerveau adulte, et inhibe la voie de signalisation Shh in vitro. Par ailleurs, une cartographie de Hip dans le cerveau de souris embryonnaire (E13.5) et adulte supporte l'hypothèse que Hip interviendrait dans la régulation négative de la voie Shh. Enfin l'expression de Hip dans des cellules exprimant l'enzyme de synthèse de l'oxide nitrique (NO) dans le cerveau mature suggère des interactions entre les voies de signalisation impliquant respectivement Hip et le neuromédiateur gazeux NO. Pour étudier le rôle de Shh in vivo sur les progéniteurs neuraux du cerveau mature, la protéine recombinante ShhN a été injectée par stéréotaxie dans le ventricule latéral (VL) de souris adultes. En plus d'une forte activation de la voie Shh, reflétée par l'augmentation de la transcription de Ptc et Gli1 dans plusieurs régions cérébrales, telles que la zone sous ventriculaire (ZSV), le striatum, le septum latéral, le corps calleux et le cortex cérébral, le nombre de cellules ayant incorporé le marqueur de prolifération Bromodésoxyuridine (BrdU), est augmenté d'un facteur 3-4 dans le corps calleux et le cortex cérébral des souris ayant reçu la protéine Shh en comparaison avec des souris contrôles. Une telle augmentation n'a pas été observée dans la ZSV, une aire de neurogenèse majeure chez l'adulte. Par ailleurs, deux jours après l'injection de ShhN, un nombre significativement plus important de cellules en prolifération exprimant le protéoglycan membranaire NG2, marqueur des précurseurs oligodendrocytaires, est observé dans le cortex cérébral des souris ayant reçu la protéine ShhN. Afin d'analyser l'effet à long terme de la surexpression continue de la protéine Shh, un vecteur adénoviral Ad5-hShh-ires-eGFP destiné à exprimer la forme humaine de la protéine Shh a été développé puis caractérisé in vitro. Ce vecteur a ensuite été délivré dans le VL de cerveau de souris adultes et quatre jours après, la protéine Shh a été détectée dans les régions épendymaire et subépendymaire. Vingt-six jours après l'injection du vecteur Ad5-hShh-ires-eGFP, la voie Shh est toujours active comme révélé par la présence de nombreuses cellules exprimant le transcrit Gli1 dans plusieurs aires cérébrales. Une augmentation de 50% du nombre de cellules BrdU+ exprimant le marqueur oligodendroglial dm20+ est détectée dans le cortex cérébral et le corps calleux des souris ayant reçu le vecteur adénoviral Ad5-hShh-ires-eGFP par rapport aux souris ayant reçu le vecteur contrôle Ad5-eGFP. Dans leur ensemble, ces résultats suggèrent la capacité de la voie Shh à stimuler les cellules oligodendrocytaires pré-matures dans plusieurs régions du cerveau de rongeurs adultes. La modulation de cette voie apparaît donc potentiellement intéressante pour le traitement des maladies affectant le lignage oligodendrocytaire.
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Goldstein, Evan Zachary. „TLR4-activated microglia have divergent effects on oligodendrocyte lineage cells“. The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468967532.
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Naglieri, Benedetta. „Complex Regulation of Pax6 Neuronal Progenitors By Rb Family Members During Corticogenesis“. Thesis, 2012. https://doi.org/10.7916/D8BP090R.
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The retinoblastoma tumor suppressor (pRB) inhibits tumorigenesis by restraining cell cycle progression via repression of the E2F transcription factor family and by promoting cell differentiation via activation of lineage-specific transcription factors. In contrast, the closely related pRB homologues, p107 and p130, are known to inhibit cell cycle progression by repressing the E2F transcription factor family, but are not known to have roles in promoting cell differentiation. Interestingly, the Rb promoter contains a critical cassette of binding sites (Sp1/Ets, ATF and E2F) that is conserved between mice and humans. Previously, our lab developed a wild type Rb promoter-LacZ transgenic reporter line (T157) that displayed dynamic and neuronal-specific expression (Agromayor et al., 2006). We generated mutant Rb promoter-LacZ transgenic lines and demonstrated that the conserved cassette controls Rb expression, positively through the Sp1/Ets site and negatively through the E2F site. Repression of the Rb promoter through this critical E2F site means that the E2F family lies both upstream and downstream of Rb, and suggests that Rb family members regulate the Rb promoter during neuronal development. To identify which Rb family member represses the Rb promoter during corticogenesis, we generated RbP-LacZ lines in genetic backgrounds deficient in various Rb family members and looked for deregulation of RbP-LacZ activity within the embryo (Aim 1). Surprisingly, RbP-LacZ activity responds in opposing ways with either loss of Rb or dual loss of p107 and p130, demonstrating that regulation of the Rb promoter by Rb family members during corticogenesis is complex. To determine whether direct or indirect mechanisms are responsible for the opposing changes in RbP-LacZ expression with loss of Rb family members in the developing cortex, we evaluated occupancy at the Rb promoter (ChIP analysis), proliferation, cell death (BrdU incorporation and TUNEL analysis) and changes in gene expression (RT-PCR) in wild type vs. mutant cortices from embryos lacking various Rb family members (Aim 2). Interestingly, we found evidence for both direct and indirect action of Rb family member inactivation on the Rb promoter. To determine if the opposing changes in RbP-LacZ activity with either loss of Rb or dual loss of p107 and p130 occurs in a cell autonomous or a non-cell autonomous manner, we optimized and analyzed primary cortical neuron cultures from wild type and mutant embryos to quantitate RbP-LacZ activity on a cell-by-cell basis (Aim 3). We compared changes in the frequency and intensity of RbP-LacZ activity, the distribution of neuronal subpopulations, identified the cells expressing RbP-LacZ activity and evaluated differences in these populations with loss of various Rb family members. Through these studies, we have discovered a complex relationship exists between Rb family members and Pax6 progenitors during corticogenesis, underscoring the intricate nature of the network connecting the Rb and E2f families in vivo.