Transcriptional mechanisms of neural stem cell maintenance and neurogenesis

神经干细胞维持和神经发生的转录机制

• 批准号: BB/K005316/1
• 负责人: Francois Guillemot
• 金额: $ 54.8万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK005316%2F1
• 关键词: Transcriptional; mechanisms; neural; stem; cell

The purpose of this project is to better understand how stem cells decide whether to multiply or to generate nerve cells. Stem cells are the crucial progenitor cells that generate all the specialized cells that form the organs in the embryo. They are also present in adult organs where they are required for maintenance and repair. Each organ has its own stem cells that generate the particular cell types of that organ. In medicine, stem cells can be used to replace cells that are damaged in diseases; for example blood stem cells are used to treat leukemias. In order to extend their usage to the treatment of other diseases, we must learn much more about how stem cells work. In particular we need to better understand the process by which a stem cell becomes specialised to generate one kind of cell rather than another. In this project, we will study how stem cells of the nervous system (called neural stem cells) become specialized in the generation of nerve cells (neurons). This process involves a profound change in the set of genes that are active: genes that present in stem cells are shut down, while genes characteristic of neurons become active. Gene activity is controlled by proteins called transcription factors. One of the main transcription factors that controls the generation of the neurons of our brains is called Ascl1. The primary purpose of this project is to understand how Ascl1 changes the set of active genes in neural stem cells so that these cells generate new neurons.Transcription factors work by binding to DNA near the genes they activate. They bring with them a multitude of other factors (called cofactors). Some of these cofactors modify the proteins that coat the DNA, others increase the contact of transcription factors with the DNA, and together they are directly involved in activating or inactivating genes. In this project, we will identify the cofactors that help the transcription factor Ascl1 activate the genes required to generate neurons. We will also identify the cofactors that prevent the inappropriate activation of genes that promote the generation of other kinds of cells. Our adult brains contain very few stem cells, which means they are limited in their ability to recover from brain damage and disease. Understanding the machinery that makes neural stem cells produce neurons can help us develop ways to replace lost brain cells. This can be done either by activating the resident stem cells, or transforming non-brain cells (e.g. skin cells) into neurons. In either case, these can then be transplanted or used to test drugs for their ability to treat neurological diseases, and hence have the potential to offer therapeutic solutions to a variety of currently untreatable conditions. This project will help in this endeavour by identifying ways to help stem cells of the brain generate more neurons.

该项目的目的是更好地了解干细胞如何决定是否繁殖或生成神经细胞。干细胞是产生形成胚胎器官的所有特化细胞的关键祖细胞。它们也存在于需要它们进行维护和修复的成人器官中。每个器官都有自己的干细胞，可以产生该器官的特定细胞类型。在医学上，干细胞可用于替代因疾病而受损的细胞；例如，血液干细胞用于治疗白血病。为了将其用途扩展到其他疾病的治疗，我们必须更多地了解干细胞的工作原理。特别是，我们需要更好地了解干细胞专门产生一种细胞而不是另一种细胞的过程。在这个项目中，我们将研究神经系统的干细胞（称为神经干细胞）如何专门生成神经细胞（神经元）。这个过程涉及一组活跃基因的深刻变化：干细胞中存在的基因被关闭，而神经元特征的基因变得活跃。基因活性由称为转录因子的蛋白质控制。控制大脑神经元生成的主要转录因子之一称为 Ascl1。该项目的主要目的是了解 Ascl1 如何改变神经干细胞中的一组活性基因，以便这些细胞产生新的神经元。转录因子通过与它们激活的基因附近的 DNA 结合来发挥作用。它们带来了许多其他因素（称为辅因子）。这些辅助因子中的一些修饰了 DNA 的蛋白质，另一些则增加了转录因子与 DNA 的接触，并且它们一起直接参与基因的激活或失活。在这个项目中，我们将鉴定帮助转录因子 Ascl1 激活生成神经元所需基因的辅助因子。我们还将确定辅助因子，以防止促进其他类型细胞生成的基因的不当激活。我们成人的大脑含有很少的干细胞，这意味着它们从脑损伤和疾病中恢复的能力有限。了解神经干细胞产生神经元的机制可以帮助我们开发替代丢失脑细胞的方法。这可以通过激活驻留的干细胞或将非脑细胞（例如皮肤细胞）转化为神经元来完成。无论哪种情况，这些都可以被移植或用于测试药物治疗神经系统疾病的能力，因此有可能为各种目前无法治疗的疾病提供治疗解决方案。该项目将通过确定帮助大脑干细胞产生更多神经元的方法来帮助实现这一目标。

项目成果

A Nuclear Role for miR-9 and Argonaute Proteins in Balancing Quiescent and Activated Neural Stem Cell States.

• DOI: 10.1016/j.celrep.2016.09.088
• 发表时间: 2016-10-25
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Katz S;Cussigh D;Urbán N;Blomfield I;Guillemot F;Bally-Cuif L;Coolen M
• 通讯作者: Coolen M

Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis.

• DOI: 10.1016/j.celrep.2015.02.025
• 发表时间: 2015-03-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Raposo AASF;Vasconcelos FF;Drechsel D;Marie C;Johnston C;Dolle D;Bithell A;Gillotin S;van den Berg DLC;Ettwiller L;Flicek P;Crawford GE;Parras CM;Berninger B;Buckley NJ;Guillemot F;Castro DS
• 通讯作者: Castro DS

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

Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal.

• DOI: 10.1101/gr.173435.114
• 发表时间: 2015-01
• 期刊: Genome research
• 影响因子: 7
• 作者: Mateo JL;van den Berg DL;Haeussler M;Drechsel D;Gaber ZB;Castro DS;Robson P;Lu QR;Crawford GE;Flicek P;Ettwiller L;Wittbrodt J;Guillemot F;Martynoga B
• 通讯作者: Martynoga B