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首页> 外文OA文献 >CARACTERISATION DU RESEAU DE SIGNALISATION IMPLIQUE DANS LA MAINTENANCE ET LA PROLIFERATION DES CELLULES SOUCHES DE LA RETINE DU XENOPE
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CARACTERISATION DU RESEAU DE SIGNALISATION IMPLIQUE DANS LA MAINTENANCE ET LA PROLIFERATION DES CELLULES SOUCHES DE LA RETINE DU XENOPE

机译：氙眼视网膜干细胞的维持和增殖所涉及的信号网络的表征

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In contrast to the adult mammals, the retina of amphibians shows continuous growth during adulthood through active neural stem cells localized in the defined niche called ciliary marginal zone (CMZ). This model offers an exceptional tool to study in vivo the molecular mechanisms involved in the maintenance and proliferation of neural stem cells during post-embryonic stages. In this order, the identification and the characterization of the signaling pathways acting in biological retinal stem cell niche is an essential step.My PhD research was divided in two main parts: the study of the interaction between the Wnt and Hedgehog pathways within the CMZ and the functional study of Yap, the downstream effector of the Hippo pathway in this model. By using genetic and pharmacological tools, the first part of this project demonstrated an unexpected antagonism between the Wnt and the Hedgehog signaling in the CMZ that regulates proliferative activity of retinal stem and progenitor cells. In this article, we propose a model in which an antagonistic interplay of Wnt and Hedgehog pathways may regulate the balance proliferation/differentiation in the post-embryonic retina. Second, gain and loss of function experiments of Yap have shown that this factor plays a key role in the regulation of temporal replication of DNA retinal stem cells. Indeed, inhibition of Yap leads to strong reduction of the S-phase length during the cell cycle associated with genomic instability. c-Myc and p53-p21 overactivation seems to be involved in this phenotype. This work also allowed us to identify a novel YAP partner, the transcriptional factor PKNOX1. We indeed propose a model in which the YAP/PKNOX1 complex may be required for the successful convening of the replication phase on stem cells, essential for the maintenance of genome integrity on the cells and their progeny.
机译：与成年哺乳动物相反，两栖动物的视网膜在成年期间通过位于称为睫毛边缘区（CMZ）的特定生态位中的活性神经干细胞显示出持续的生长。该模型提供了一个出色的工具，可在体内研究胚胎后阶段神经干细胞维持和增殖的分子机制。以此顺序，识别和表征生物视网膜干细胞生态位中的信号通路是必不可少的步骤。我的博士学位研究分为两个主要部分：CMZ中Wnt和Hedgehog通路之间相互作用的研究和Yap的功能研究，即该模型中Hippo途径的下游效应子。通过使用遗传和药理学工具，该项目的第一部分证明了CMZ中Wnt和Hedgehog信号传导之间存在意想不到的拮抗作用，该信号传导调节视网膜干细胞和祖细胞的增殖活性。在本文中，我们提出了一个模型，其中Wnt和Hedgehog途径的拮抗相互作用可能调节胚后视网膜的平衡增殖/分化。其次，Yap的功能获得和丧失实验表明，该因子在调节DNA视网膜干细胞的时间复制中起关键作用。实际上，抑制Yap导致在与基因组不稳定性相关的细胞周期中S期长度的强烈减少。 c-Myc和p53-p21过度激活似乎与该表型有关。这项工作还使我们能够鉴定出新型的YAP伴侣，转录因子PKNOX1。我们确实提出了一个模型，其中可能需要YAP / PKNOX1复合物才能在干细胞上成功召集复制阶段，这对于维持细胞及其后代的基因组完整性至关重要。

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    Cabochette Pauline;

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