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Sox transcription factor function and redundancy in the central nervous system

Sox转录因子在中枢神经系统中的功能和冗余

基本信息

批准号：
BB/N007069/1
负责人：
Steven Russell
金额：
$ 63.2万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN007069%2F1
关键词：
Sox transcription factor function redundancy

项目摘要

During the early development of complex multicellular organisms such as humans, cells must adopt particular fates in order to generate the variety of tissues and organs necessary to build the embryo. Early in development, specific sets of cells gain the ability to subsequently develop the various cell types of the nervous system. Once specified, this cell population will divide in an undifferentiated state, known as neural stem cells, to generate sufficient cells that can subsequently be directed to make neurons and other cell types necessary to build a nervous system. Not only are these neural stem cells important for normal development, they may also be isolated or generated from other cell types and grown in the laboratory. It is hoped that neural stem cells will in the future provide a route for the treatment of human neurological disorders that are currently intractable. Underpinning the developmental choices cells make and their maintenance of the stem cell state are sets of proteins known as transcription factors (TFs) that act in the cell nucleus to control the specific sets of genes that define the neural state. One such class of TFs important in neural stem cells are known as Sox proteins. While there has been considerable work aimed at addressing how Sox proteins act to control the stem cell state in mammals, this work is complicated by the fact that three closely related proteins are present in neural cells at the same time and compensate for each other when mutations are made. This makes it difficult to understand how these proteins function and this is an important issue since they play such a crucial role in stem cell biology.The fruit fly, Drosophila melanogaster, is a model system widely used in the laboratory to study basic aspects of the genetics and development of complex multicellular animals. In general, the fly offers a much simpler system for studying basic biological processes since it is easy to maintain, easy to manipulate genetically and does not raise concerns about excessive animal use in experimental work. Over the years it has been established that many of the cell fate choices fly cells make are governed by sets of regulatory proteins that are very closely related to mammalian proteins performing similar roles. In the case of Sox proteins acting in the nervous system, we have shown the fly offers a simpler experimental system that still shares some of the complexity shown by mammalian proteins. Instead of three Sox proteins, the fly has only two, and we have shown that mouse and human Sox proteins are able to efficiently function in the fly.Sox proteins function by controlling sets of genes that define the phenotype of a cell and our recent work has shown that Sox proteins in fly and mouse neural stem cells control many of the same genes. However, despite a considerable amount of work on both mammalian and fly Sox proteins we still have a very poor mechanistic understanding of how they act to regulate their target genes. If we are to generate and manipulate neural stem cells in that lab for therapeutic uses, it is important we fully understand the roles Sox proteins play, particularly since they are now often used to produce and maintain stem cells. We will perform a detailed analysis of both fly and mammalian Sox proteins in the Drosophila model to understand more fully how they recognize the specific genes they control in the nucleus, how related Sox proteins act together and are able to compensate for each others loss and explore exactly why important cells types such as neural stem cells need to express closely related Sox proteins. Although our work is performed in the fly, the fact that Sox function is so similar in fly and mouse means that what we learn will be relevant to human biology.

在复杂的多细胞生物（如人类）的早期发育过程中，细胞必须采取特定的命运，以产生构建胚胎所需的各种组织和器官。在发育的早期，特定的细胞群获得了随后发育神经系统各种细胞类型的能力。一旦被指定，这个细胞群将在未分化状态下分裂，称为神经干细胞，以产生足够的细胞，随后可以定向制造神经元和建立神经系统所必需的其他细胞类型。这些神经干细胞不仅对正常发育很重要，它们也可以从其他细胞类型中分离或产生，并在实验室中生长。人们希望神经干细胞在未来能为治疗目前难以治愈的人类神经系统疾病提供一条途径。支持细胞做出的发育选择及其对干细胞状态的维持的是被称为转录因子（TF）的蛋白质组，其在细胞核中起作用以控制定义神经状态的特定基因组。在神经干细胞中重要的一类TF被称为Sox蛋白。虽然已经有相当多的工作旨在解决Sox蛋白如何控制哺乳动物的干细胞状态，但这项工作由于三种密切相关的蛋白质同时存在于神经细胞中并在突变时相互补偿的事实而变得复杂。这使得人们很难理解这些蛋白质的功能，这是一个重要的问题，因为它们在干细胞生物学中起着至关重要的作用。果蝇（Drosophila melanogaster）是一种模型系统，广泛用于实验室研究复杂多细胞动物的遗传学和发育的基本方面。总的来说，苍蝇提供了一个更简单的系统来研究基本的生物过程，因为它很容易维护，很容易进行遗传操作，并且不会引起人们对实验工作中过度使用动物的担忧。多年来，人们已经确定，苍蝇细胞所做的许多细胞命运选择是由一组调节蛋白决定的，这些调节蛋白与哺乳动物蛋白非常密切相关，发挥着类似的作用。在Sox蛋白在神经系统中起作用的情况下，我们已经证明果蝇提供了一个更简单的实验系统，仍然具有哺乳动物蛋白质所显示的一些复杂性。而不是三个Sox蛋白，苍蝇只有两个，我们已经表明，小鼠和人类的Sox蛋白能够有效地发挥作用的苍蝇。Sox蛋白的功能，通过控制一组基因，定义一个细胞的表型和我们最近的工作表明，Sox蛋白在苍蝇和小鼠神经干细胞控制许多相同的基因。然而，尽管对哺乳动物和果蝇Sox蛋白进行了大量的工作，但我们仍然对它们如何调节其靶基因的机制了解甚少。如果我们要在实验室中产生和操纵神经干细胞用于治疗用途，那么我们充分了解Sox蛋白所起的作用是很重要的，特别是因为它们现在经常用于产生和维持干细胞。我们将在果蝇模型中对果蝇和哺乳动物的Sox蛋白进行详细分析，以更全面地了解它们如何识别它们在细胞核中控制的特定基因，相关的Sox蛋白如何共同作用并能够补偿彼此的损失，并探索为什么重要的细胞类型，如神经干细胞需要表达密切相关的Sox蛋白。虽然我们的工作是在苍蝇中进行的，但Sox功能在苍蝇和小鼠中如此相似的事实意味着我们所了解的将与人类生物学有关。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The evolutionally-conserved function of group B1 Sox family members confers the unique role of Sox2 in mouse ES cells.

DOI：
10.1186/s12862-016-0755-4
发表时间：
2016-08-31
期刊：
BMC evolutionary biology
影响因子：
3.4
作者：
Niwa H;Nakamura A;Urata M;Shirae-Kurabayashi M;Kuraku S;Russell S;Ohtsuka S
通讯作者：
Ohtsuka S

The evolution of Sox gene repertoires and regulation of segmentation in arachnids

蛛形纲动物 Sox 基因库的进化和节段调控

DOI：
10.1101/2020.06.04.133389
发表时间：
2020
期刊：
影响因子：
0
作者：
Baudouin-Gonzalez L
通讯作者：
Baudouin-Gonzalez L

Sox enters the picture.

DOI：
10.7554/elife.41136
发表时间：
2018-10-01
期刊：
eLife
影响因子：
7.7
作者：
Kaufholz F;Turetzek N
通讯作者：
Turetzek N

The Evolution of Sox Gene Repertoires and Regulation of Segmentation in Arachnids.

DOI：
10.1093/molbev/msab088
发表时间：
2021-07-29
期刊：
Molecular biology and evolution
影响因子：
10.7
作者：
Baudouin-Gonzalez L;Schoenauer A;Harper A;Blakeley G;Seiter M;Arif S;Sumner-Rooney L;Russell S;Sharma PP;McGregor AP
通讯作者：
McGregor AP

Engineering the Drosophila Genome for Developmental Biology.