Role of Sox2 in the direct lineage reprogramming of astroglia into neurons

Sox2 在星形胶质细胞直接谱系重编程为神经元中的作用

• 批准号: 66495936
• 负责人: Professor Dr. Benedikt Berninger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/66495936?language=en
• 关键词: Role; Sox2; direct; lineage; reprogramming

Our studies during the last funding period have demonstrated that immature astroglia can be completely and stably lineage reprogrammed into functional neurons by a single neurogenic transcription factor (TF). In contrast, in more mature astroglia single neurogenic TFs fail to induce reprogramming. However, proneural gene-iduced reprogramming success can be greatly enhanced by co-expression of Sox2, a TF essential for pluripotency reprogramming as well as embryonic and neural stem cell maintenance. In the present proposal we aim at obtaining insights into the molecular mechanisms underlying the Sox2-mediated enhancement of astroglia-to-neuron lineage conversion by analyzing changes in the astrocyte transcriptome in response to Sox2. Furthermore we plan to identify binding partners of Sox2 in astrocytes by immunoprecipitation followed by mass spectrometry and to study their binding to putative Sox2 binding sites in promoter regions of identified Sox2 target genes in astrocytes by chromatin immunoprecipitation. Given the suggested programmatic role of chromatin remodelers during developmental transitions we finally will assess how the brahma-associated factor (BAF) complex differs between astrocytes and other cells and whether its composition changes with maturation. On basis of this data we will examine whether modifying the BAF complex composition in astrocytes towards either an embryonic stem cell- or neural precursorspecific state facilitates direct lineage reprogramming of astrocytes into neurons by proneural genes.

我们在上一次资助期间的研究表明，未成熟的星形胶质细胞可以通过单一的神经源性转录因子(Tf)完全和稳定地重新编程为功能神经元。相比之下，在更成熟的星形胶质细胞中，单一的神经源性因子无法诱导重新编程。然而，通过共表达Sox2可以大大提高神经基因诱导的重编程成功，Sox2是一种多能性重编程以及胚胎和神经干细胞维持所必需的转铁蛋白。在目前的建议中，我们旨在通过分析星形胶质细胞转录组对Sox2的响应变化来深入了解Sox2介导的促进星形胶质细胞向神经元转化的分子机制。此外，我们计划通过免疫沉淀和质谱仪鉴定星形胶质细胞中Sox2的结合伙伴，并通过染色质免疫沉淀研究它们与星形胶质细胞中已鉴定的Sox2靶基因启动子区域中可能的Sox2结合位点的结合。鉴于染色质重构体在发育转变中的程序性作用，我们最终将评估星形胶质细胞和其他细胞之间的梵天相关因子(BAF)复合体是如何不同的，以及它的组成是否随着成熟而变化。在这些数据的基础上，我们将研究是否将星形胶质细胞中的BAF复合体成分修改为胚胎干细胞或神经前体特异性状态，有助于通过原神经基因将星形胶质细胞直接重新编程为神经元。

项目成果

SoxC transcription factors are required for neuronal differentiation in adult hippocampal neurogenesis.

• DOI: 10.1523/jneurosci.4679-11.2012
• 发表时间: 2012-02-29
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Mu L;Berti L;Masserdotti G;Covic M;Michaelidis TM;Doberauer K;Merz K;Rehfeld F;Haslinger A;Wegner M;Sock E;Lefebvre V;Couillard-Despres S;Aigner L;Berninger B;Lie DC
• 通讯作者: Lie DC