The Role of Nanog in Establishment and Patterning of Embryonic Pluripotency

Nanog 在胚胎多能性建立和模式化中的作用

基本信息

批准号：
MR/L001047/1
负责人：
Andrew Johnson
金额：
$ 64.15万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL001047%2F1
关键词：
Role Nanog Establishment Patterning Embryonic

项目摘要

Embryonic stem (ES) cells can become any cell in the body, and so they have great potential as a tool for regenerative medicine to repair tissue damaged by injury or disease. A major goal of modern medicine, therefore, is to understand how to harvest the potential of embryonic stem cells for therapeutic purposes. The signature ability of ES cells to become other cells is called pluripotency, which is carefully regulated by protein factors, called pluripotency factors, which control the genes that regulate ES cell behaviour. We are working to identify how those genes are controlled, and we have focused on one of the most important pluripotency factors, called Nanog, a master regulator of stem cell behaviour.ES cells resemble the cells that make up early embryos, and so by understanding how embryos develop it becomes it is possible to learn how to regulate ES cells to make specific types of adult cells. However, to understand how ES cells become pluripotent, it is necessary to consider the establishment of pluripotency in the embryo itself. However, the embryos of humans, and other mammals, are very small, and they develop inside the mother, so they are very difficult to access and to manipulate. A way around this problem is use the embryos of other species, whose cells resemble those of human embryos, but which are much easier to work with. This approach has been used for decades in biology to identify the function of genes in embryonic cells. However, we discovered that the embryos of frogs and fish, which most investigators use in the lab, do not contain pluripotent cells. For this reason we had to develop a novel experimental system using embryos from axolotls.Mammals evolved from amphibians, of which there are two types, frogs and salamanders. These two types of amphibians last had a common relative 250 million years ago. Since then, frogs have evolved many traits are unique to them, however salamanders have remained relatively unchanged since they first walked the earth, and they evolved into reptiles and mammals. For this reason, the genes that control the development of embryos from salamanders and mammals are almost the same. In fact, axolotls are representative salamanders, and we have shown that they contain pluripotent cells that are basically the same as the ones that develop in human embryos. Also, importantly, they contain a Nanog gene, which for reasons that are not entirely clear, does not exist in frog embryos. For our purposes axolotl embryos are a perfect tool to understand how pluripotent cells respond to signals that tell them to become other cell types. We are using axolotl embryos to study how Nanog is regulated.Axolotl embryos develop outside of the mother, so hundreds of embryos can be collected without harming the animals. Also, the embryos are enormous, about 10,000 times the size of human embryos, so it is very easy to dissect the cells you want to study in the lab. The axolotl experimental system that we developed is unique in the UK, and we are the only group in the world currently using it to understand pluripotency. When we isolated the Nanog gene from axolotls we showed that it works as well as human Nanog in controlling the behaviour of ES cells. But ES cells are not embryos, and we have the unique opportunity to understand how Nanog functions in a normal embryo, the embryo of an axolotl.In this project we will take the pluripotent cells in axolotl embryos and induce them to become specific types of differentiated cells using solutions that contain the molecules that control development of normal embryos. We will then analyse how the loss of Nanog changes the response to these signals. By identifying how the cells respond we will understand the necessary first step in the establishment of pluripotency, and this will provide cues for how to produce human tissue for regenerating damaged body parts.

胚胎茎（ES）细胞可以成为体内的任何细胞，因此它们具有巨大的潜力作为再生医学的工具，可以修复受伤或疾病受损的组织。因此，现代医学的主要目标是了解如何以治疗目的收获胚胎干细胞的潜力。 ES细胞成为其他细胞的签名能力称为多能性，该多能由蛋白质因子（称为多能因素）仔细调节，这些因子控制了调节ES细胞行为的基因。我们正在努力确定这些基因的控制方式，并且我们专注于最重要的多能性因子之一，称为Nanog，Nanog，干细胞行为的主要调节剂。ES细胞类似于构成早期胚胎的细胞，因此，通过了解胚胎如何发展胚胎开发的方式是可以使ES细胞成为可能使ES细胞成为特定类型的成人细胞的可能性。但是，要了解ES细胞如何变得多功能，有必要考虑在胚胎本身中建立多能性。但是，人类和其他哺乳动物的胚胎非常小，并且在母亲的内部发展，因此它们很难进入和操纵。解决这个问题的一种方法是使用其他物种的胚胎，它们的细胞类似于人类胚胎的细胞，但它们更容易使用。几十年来，这种方法已在生物学中用于鉴定基因在胚胎细胞中的功能。但是，我们发现大多数研究人员在实验室中使用的青蛙和鱼类的胚胎不包含多能细胞。因此，我们必须使用来自Axolotl的胚胎开发一种新型的实验系统。这两种两种两种两种两种类型的相对相对2.5亿年前。从那时起，青蛙就发展出许多特征是独一无二的，但是自从他们第一次走上地球以来，萨拉曼德人一直相对不变，它们演变成爬行动物和哺乳动物。因此，控制来自sal和哺乳动物的胚胎发展的基因几乎相同。实际上，Axolotls是代表性的Salamanders，我们已经表明它们包含多能细胞，这些细胞基本上与在人类胚胎中发育的细胞相同。同样，重要的是，它们包含一个纳米基因，其原因尚不完全清楚，在青蛙胚胎中不存在。出于我们的目的，Axolotl胚胎是了解多能单元格如何响应信号的理想工具，该信号告诉它们成为其他细胞类型。我们正在使用Axolotl胚胎研究纳米的调节方式。轴突胚胎在母亲之外发展，因此可以收集数百个胚胎而不会损害动物。同样，胚胎是巨大的，大约是人类胚胎的大约10,000倍，因此很容易剖析要在实验室学习的细胞。我们开发的Axolotl实验系统在英国是独一无二的，我们是目前使用它来了解多能性的世界上唯一的群体。当我们从Axolotls分离Nanog基因时，我们表明它在控制ES细胞的行为方面起作用以及人类Nanog。但是ES细胞不是胚胎，我们有独特的机会来了解Nanog在正常胚胎中的功能，即Axolotl的胚胎。在该项目中，我们将采用axolotl胚胎中的多能细胞，并诱导它们成为特定类型的分化细胞，其中包含控制正常胚胎发育的分子的溶液。然后，我们将分析Nanog的丢失如何改变对这些信号的响应。通过确定细胞的响应方式，我们将了解建立多能性的必要第一步，这将为如何生产人体组织来再生受损的身体部位。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

LINE-1 transcription in round spermatids is associated with accretion of 5-carboxylcytosine in their open reading frames.

DOI：
10.1038/s42003-021-02217-8
发表时间：
2021-06-07
期刊：
Communications biology
影响因子：
5.9
作者：
Blythe MJ;Kocer A;Rubio-Roldan A;Giles T;Abakir A;Ialy-Radio C;Wheldon LM;Bereshchenko O;Bruscoli S;Kondrashov A;Drevet JR;Emes RD;Johnson AD;McCarrey JR;Gackowski D;Olinski R;Cocquet J;Garcia-Perez JL;Ruzov A
通讯作者：
Ruzov A

5-Carboxylcytosine levels are elevated in human breast cancers and gliomas.

DOI：
10.1186/s13148-015-0117-x
发表时间：
2015
期刊：
Clinical epigenetics
影响因子：
5.7
作者：
Eleftheriou M;Pascual AJ;Wheldon LM;Perry C;Abakir A;Arora A;Johnson AD;Auer DT;Ellis IO;Madhusudan S;Ruzov A
通讯作者：
Ruzov A

Stochastic specification of primordial germ cells from mesoderm precursors in axolotl embryos.

DOI：
10.1242/dev.105346
发表时间：
2014-06
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Chatfield J;O'Reilly MA;Bachvarova RF;Ferjentsik Z;Redwood C;Walmsley M;Patient R;Loose M;Johnson AD
通讯作者：
Johnson AD

Primordial germ cells: the first cell lineage or the last cells standing?