Regulation and function of the stem cell activation factor Ascl1 in constitutive and injury-induced adult neurogenesis

干细胞激活因子 Ascl1 在组成性和损伤诱导的成体神经发生中的调节和功能

• 批准号: MR/M023907/1
• 负责人: Francois Guillemot
• 金额: $ 73.19万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM023907%2F1
• 关键词: Regulation; function; stem; cell; activation

The purpose of this project is to understand why new nerve cells are produced only in particular areas of the brain and why injuries cannot be repaired in other brain areas. Nerve cells are produced by special cells called stem cells that retain the properties of cells in the embryo to divide and produce various types of specialized cells. Stem cells are only found in limited areas of the brain where they divide throughout life to produce new nerve cells. We have found a protein called Ascl1 that stimulates the divisions of the stem cells and is therefore important for the production of new nerve cells. Our collaborators at the Karolinska Institute in Sweden have also found that the same protein Ascl1 is also present after a stroke in another brain region and in a distinct type of cells called glial cells. Some of these glial cells behave like stem cells when Ascl1 is present after stroke, as they divide and produce new nerve cells, but others do not react to the presence of Ascl1 and fail to produce nerve cells. To help the brain repair the damages caused by strokes, there is clearly a need to improve how glial cells react to the injury and to help them become more like stem cells. For this, we need to understand better how Ascl1 works. With this project, we want first to understand why Ascl1 is present in stem cells and in some glial cells after a stroke but not in others. We will therefore study the molecules that control in which brain cells Ascl1 is found. Second, we want to understand why, when Ascl1 is present in glial cells, some behave like stem cells and divide while other do not react to the presence of Ascl1 and continue to behave like normal glial cells. Ascl1 is a transcription factor, which means that it controls the activity of many genes in the cells where it is present, and these genes in turn control the behavior of the cells such as their divisions. We will therefore examine the genes that are controlled by Ascl1 in stem cell-like glial cells that respond to Ascl1 and we will find out why the same genes are not controlled by Ascl1 in other glial cells.We expect our research to lead to a better understanding of how the brain reacts to injuries such as strokes and why it has a limited ability to replace the nerve cells lost with new cells. In the longer term, we hope to have learned enough of the effect of stroke on glial cells to help devise treatments that convert more glial cells into stem cells and help the brain repair itself.

这个项目的目的是了解为什么新的神经细胞只在大脑的特定区域产生，以及为什么大脑其他区域的损伤不能修复。神经细胞是由一种叫做干细胞的特殊细胞产生的，这种细胞保留了胚胎细胞的特性，可以分裂并产生各种类型的特化细胞。干细胞只存在于大脑的有限区域，在那里它们一生都在分裂以产生新的神经细胞。我们发现了一种叫做Ascl1的蛋白质，它能刺激干细胞的分裂，因此对新神经细胞的产生很重要。我们在瑞典卡罗林斯卡研究所的合作者还发现，中风后，在大脑的另一个区域和一种叫做神经胶质细胞的不同类型的细胞中，也存在相同的Ascl1蛋白。中风后，当Ascl1存在时，这些神经胶质细胞中的一些表现得像干细胞一样，它们分裂并产生新的神经细胞，但另一些对Ascl1的存在没有反应，不能产生神经细胞。为了帮助大脑修复中风造成的损伤，显然需要改善神经胶质细胞对损伤的反应，并帮助它们变得更像干细胞。为此，我们需要更好地理解Ascl1是如何工作的。在这个项目中，我们首先想了解为什么Ascl1存在于中风后的干细胞和一些神经胶质细胞中，而不存在于其他细胞中。因此，我们将研究控制脑细胞中发现Ascl1的分子。其次，我们想要理解为什么当Ascl1存在于神经胶质细胞中时，一些表现得像干细胞一样并分裂，而另一些对Ascl1的存在没有反应并继续表现得像正常的神经胶质细胞一样。Ascl1是一种转录因子，这意味着它控制着它所在细胞中许多基因的活性，而这些基因反过来又控制着细胞的行为，比如它们的分裂。因此，我们将检查对Ascl1有反应的干细胞样神经胶质细胞中由Ascl1控制的基因，我们将发现为什么相同的基因在其他神经胶质细胞中不受Ascl1控制。我们希望我们的研究能让我们更好地理解大脑对中风等损伤的反应，以及为什么大脑用新细胞替换失去的神经细胞的能力有限。从长远来看，我们希望对中风对神经胶质细胞的影响有足够的了解，以帮助设计出将更多神经胶质细胞转化为干细胞的治疗方法，并帮助大脑自我修复。

项目成果

Return to quiescence of mouse neural stem cells by degradation of a proactivation protein.

• DOI: 10.1126/science.aaf4802
• 发表时间: 2016-07-15
• 期刊: Science (New York, N.Y.)
• 作者: Urbán N;van den Berg DL;Forget A;Andersen J;Demmers JA;Hunt C;Ayrault O;Guillemot F
• 通讯作者: Guillemot F

Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration.

NIPBL与ZFP609和Integrator复合物相互作用，以调节皮质神经元迁移。

• DOI: 10.1016/j.neuron.2016.11.047
• 发表时间: 2017-01-18
• 期刊: Neuron
• 影响因子: 16.2
• 作者: van den Berg DLC;Azzarelli R;Oishi K;Martynoga B;Urbán N;Dekkers DHW;Demmers JA;Guillemot F
• 通讯作者: Guillemot F

Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population.

细胞行为的协调变化确保了海马干细胞种群的终身维持。

• DOI: 10.1016/j.stem.2021.01.003
• 发表时间: 2021-05-06
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Harris L;Rigo P;Stiehl T;Gaber ZB;Austin SHL;Masdeu MDM;Edwards A;Urbán N;Marciniak-Czochra A;Guillemot F
• 通讯作者: Guillemot F