Transcriptional Control of Adult Neural Stem Cells

描述（由申请人提供）：神经干细胞存在于成人大脑中，并不断产生新的神经元，对多种生理和病理刺激作出反应，可能参与学习记忆、癫痫、抑郁和脑损伤后重塑。最近的数据也证明了神经干细胞和致命的脑肿瘤之间的联系。该应用程序的长期目标是了解成体神经干细胞的调节及其在正常或病变条件下的作用。转录因子作为多种细胞外和细胞内信号通路的整合者，通过与基因组的直接相互作用，在细胞类型规范、增殖和分化中起着关键作用。我们的研究将使用其中一种转录因子作为分子工具。我们和其他人证明了孤儿核受体TLX （NR2E1）对于神经源性龛中成体神经干细胞的维持和增殖是绝对必需的。我们进一步发现依赖tlx的成人神经发生有助于空间学习和记忆。通过采用最先进的分子、细胞和小鼠遗传方法，本文描述的研究试图理解：1)神经干细胞规范和维持的转录逻辑；2) tlx依赖性神经干细胞在脑相关疾病中的作用。这项工作的结果将为我们对神经干细胞生物学及其在疾病条件下的作用的理解提供新的见解。这些知识对于实现以这些干细胞为治疗目标的承诺至关重要。

DESCRIPTION (provided by applicant): Neural stem cells exist in the adult brain and continually generate new neurons, which respond to multiple physiological and pathological stimulations and are potentially involved in learning and memory, epilepsy, depression, and brain remodeling after injury. Most recent data also demonstrate an interconnection between neural stem cells and deadly brain tumors. The long-term goal of this application is to understand the regulation of adult neural stem cells and their roles under normal or diseased conditions. As integrators of multiple extracellular and intracellular signaling pathways and through direct interaction with the genome, transcription factors play key roles in cell type specification, proliferation, and differentiation. Our research will use one of these transcription factors as a molecular tool. We and others demonstrated that orphan nuclear receptor TLX (NR2E1) is absolutely required for the maintenance and proliferation of adult neural stem cells in neurogenic niches. We further showed that TLX-dependent adult neurogenesis contributes to spatial learning and memory. By employing the most advanced molecular, cellular and mouse genetic approaches, the studies described here seek to understand: 1) the transcriptional logic underlying the specification and maintenance of neural stem cells; and 2) the role of TLX-dependent neural stem cells in brain-related diseases. Results from this work will provide novel insights into our understanding of the biology of neural stem cells and their role under diseased conditions. Such knowledge will be pivotal to fulfill the promise of targeting these stem cells for therapeutics.