FOXO3 est un facteur de transcription important pour la réponse au stress, la régulation de la différenciation et de la survie cellulaires qui a des effets neuroprotecteurs dans plusieurs modèles de maladies neurodégénératives, dont la maladie de Huntington (MH). Les effets neuroprotecteurs de FOXO3 sont réprimés dans la MH par une activité anormale de Ryk, un récepteur Wnt important pour la neurogenèse, par la liaison du domaine intracellulaire de Ryk à la ?-caténine, un co-facteur de FOXO3. L'objectif principal de ce travail est d'étudier les effets de la huntingtine mutée (mHTT) sur le répertoire des cibles directes humaines de FOXO3 à l'aide d'un modèle des phases développementales de la MH, à savoir des cellules souches neurales isogéniques issues de cellules souches pluripotentes induites. En formant un complexe tripartite avec la ?-caténine et FOXO3, Ryk agit comme un co-régulateur de FOXO3 en conditions normales ou pathologiques. L'analyse des cibles directes de FOXO3 montre une reprogrammation de ces cibles avec des pertes et des gains dans des voies de signalisation qui sont connues pour leur rôle dans la MH, notamment les voies de régulation de la prolifération cellulaire. Ces résultats montrent que la régulation des gènes par FOXO3 est fortement modifiée dans les cellules qui expriment la mHTT. Cela ouvre la voie à l'étude des mécanismes d'homéostase cellulaire sous contrôle de FOXO3 dans les neurones en différenciation et leur impact sur l'activité des neurones adultes. Plus largement, ces résultats permettent de mieux comprendre la dynamique moléculaire de la MH et les effets de reprogrammation moléculaire sur la différenciation et l'activité neuronale. / FOXO3 is an important transcription factor for stress response, the regulation of differentiation and cell survival that has neuroprotective effects in several models of neurodegenerative diseases, including Huntington’s disease (HD). The neuroprotective effects of FOXO3 in HD are repressed by abnormal signaling from the Wnt receptor Ryk by the binding of the intracellular domain of Ryk to the β-catenin, a cofactor of FOXO3.The aim of this work was to explore the effect of the mutant huntingtin (mHTT) on the repertoire of direct FOXO3 targets (F3Ts) using a model of developmental stage of HD, namely HD isogenic neural stem cells derived from Huntington’s Induced Pluripotent Stem cells. Forming a tripartite complex with β-catenin and FOXO3, Ryk acts as a co-regulator of FOXO3 in normal or pathological condition. Analysis of direct FOXO3 targets shows reprogramming of these targets with losses and gains in signaling pathways that are known to role in HD, including regulatory pathways of cell proliferation. These results show that gene regulation by FOXO3 is heavily modified in cells expressing the mutant huntingtin. Our findings open the way for a comprehensive study of cellular homeostasis mechanisms under the control of FOXO3 in neural differentiation and their impact on the activity of adult neurons. More broadly, these results provide insight into the molecular dynamics of MH and the effects of molecular reprogramming in differentiation and neuronal activity.

Thesis (MA (Journalism))--University of Stellenbosch, 2006. / Moral questions arising from advances in science and technology are proliferating exponentially. Much controversy surrounds the ways in which biotechnology is used to eradicate a vast range of diseases and injuries. Stem cell research is one such way. Throughout the world stem cell research has been met with varying responses that range from opposition and criticism to approval and advocacy. As a result, it has attracted significant attention from the news media. The media have been accused of bias by focusing only on the controversial aspects of the research as opposed to reporting fully and fairly on the remarkable scientific advances. In this study I look at the patterns of media attention paid to stem cell research in the international weekly magazine Time between November 1998 and September 2005 inclusive. Contrary to the results expected on the basis of my literature study which pointed out the notion that the media tend to focus on sensational news more than non-controversial issues, I found that Time did a fair job in reporting on the scientific aspects of stem cell research. The percentage content of articles by year, focusing on scientific information of stem cells, dominated other news frames. The two years following the 2000 and 2004 American presidential elections, are however marked by the dominance of policy frames. This study found that Time covered controversial issues like embryonic stem cell research, public funding debates and political policy development in direct relation to their rise and fall on the political agenda in the United States.