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Functional role(s) of oestrogen signalling on neuronal progenitor cell development and fate in the brain

雌激素信号对大脑神经祖细胞发育和命运的功能作用

基本信息

批准号：
BB/L020637/1
负责人：
Charles Tyler
金额：
$ 59.51万
依托单位：
UNIVERSITY OF EXETER
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=BB%2FL020637%2F1
关键词：
Functional role oestrogen signalling neuronal

项目摘要

Nerve cells (called neurons) form in the brain principally during embryo development but they can also be synthesised in the adult brain. Defects in the process of neuron synthesis (neurogenesis) have been linked with various brain diseases, psychiatric illnesses and addictions. Neurogenesis is also critically involved in the repair of an injured brain. One type of cell, called radial glial cells (RGCs) can give rise to all types of neurons in the cerebral cortex of the brain but how this is controlled is not well understood. Recently, hormones, called oestrogens, have been indicated to play important roles in RGCs and in neurogenesis.In this project we will apply genetically engineered zebrafish models to investigate the roles of oestrogen in neurogenesis and brain development, investigating also for sex related differences. We are using zebrafish for this work because of the relative ease to create transgenic animals and the fact that there is a high neurogenic activity in the brain throughout life. We have already successfully developed one genetically engineered (transgenic) zebrafish in which cells responsive to oestrogen produce a green fluorescent protein (GFP) that can be detected using imaging methods in living animals and in real time. Using this model we will establish the role of oestrogens in the RGCs in the telecephalon and identify the different cells in the brain responsive to oestrogens and how they develop. We will also apply a method called two-photon microscopy to selectively remove the oestrogen responsive RGCs in the telecephalon and investigate subsequent effects on brain development to help establish their function. We will then develop a new transgenic zebrafish model with a different genetic insert that prolongs the green fluorescent signal generated in response to oestrogen exposure. This will enable us to follow the fate of the oestrogen responsive RGCs and other neural cells of early life in the brain of juvenile and adult fish. We will also use this model to investigate for differences that occur between males and females.We will develop a further, more complex (triple), transgenic zebrafish that will enable us to identify activity in oestrogen responding neurons. This model includes two fluorescent colours, red identifying oestrogen responsive neurons and green identifying when these cells are active (produced in response to increased levels of calcium in the cell). Using this fish we will investigate the roles of oestrogen responding neurons in smell, including assessing for sex related differences. We will also apply a technique to block oestrogen action responsive neurons in the telecephalon during early life to establish how this affects their subsequent development and function in smell.Applying these transgenic models, finally we will initiate studies into the effects of exposure to so called endocrine disrupting chemicals (EDCs), for which there is widespread health concern, on oestrogen responding neurons and their subsequent fate and function. The research will be significant interest to a diverse audience including academic and industry researchers, and the medical profession, by provision of new models to study neurogenesis and the roles of an important group of environmental chemicals on human health. It will also be of strong interest to industry and government regulatory bodies, as the models develop could be applied for advancing risk assessment of chemicals with oestrogenic activity, supporting evidence-based decision-making for those chemicals. The wider public will benefit also from this research from improved understanding of neurological conditions and better evidence of chemical effects that may affect their own health. The models developed will provide more integrative systems for chemical effects analysis with great potential for reducing the numbers of vertebrate animals used in testing.

神经细胞(称为神经元)主要在胚胎发育期间在大脑中形成，但也可以在成人大脑中合成。神经元合成(神经发生)过程中的缺陷与各种大脑疾病、精神疾病和成瘾有关。神经再生在修复受伤的大脑中也起着关键作用。一种称为放射状胶质细胞(RGC)的细胞可以在大脑皮层中产生各种类型的神经元，但这是如何控制的还不是很清楚。最近，被称为雌激素的激素在视网膜节细胞和神经发生中发挥着重要的作用。在这个项目中，我们将应用基因工程斑马鱼模型来研究雌激素在神经发生和脑发育中的作用，并调查与性别有关的差异。我们之所以使用斑马鱼进行这项工作，是因为创造转基因动物相对容易，而且在整个生命过程中，大脑中都有很高的神经源性活动。我们已经成功地开发出一种转基因斑马鱼，在这种斑马鱼中，细胞对雌激素做出反应，产生一种绿色荧光蛋白(GFP)，可以在活体动物中使用成像方法进行实时检测。利用这个模型，我们将确定雌激素在远脑节细胞中的作用，并确定大脑中不同的细胞对雌激素的反应以及它们是如何发育的。我们还将应用一种名为双光子显微镜的方法来选择性地移除远头脑中对雌激素反应的视网膜节细胞，并研究随后对大脑发育的影响，以帮助确定它们的功能。然后，我们将开发一种新的转基因斑马鱼模型，该模型具有不同的基因插入，延长了雌性激素暴露时产生的绿色荧光信号。这将使我们能够跟踪雌激素反应的RGC和其他早期生命的神经细胞在幼鱼和成鱼大脑中的命运。我们还将利用这个模型来研究雄性和雌性之间的差异。我们将开发出更复杂(三重)的转基因斑马鱼，这将使我们能够识别雌激素反应神经元的活动。这个模型包括两种荧光颜色，红色标识雌激素反应神经元，绿色标识这些细胞活跃时(产生于细胞内钙水平的增加)。利用这种鱼，我们将研究雌激素反应神经元在嗅觉中的作用，包括评估性相关的差异。我们还将应用一种技术来阻断远程脑部早期生命中的雌激素反应神经元，以确定这是如何影响它们随后的发育和嗅觉功能的。应用这些转基因模型，最后我们将开始研究暴露于所谓的内分泌干扰物(EDCs)对雌激素反应神经元及其随后的命运和功能的影响。这项研究将通过提供新的模型来研究神经发生和一组重要的环境化学物质对人类健康的作用，从而引起包括学术和行业研究人员在内的不同受众的极大兴趣。这也将引起行业和政府监管机构的浓厚兴趣，因为开发的模型可以用于推进对具有雌激素活性的化学品的风险评估，支持对这些化学品的循证决策。更广泛的公众也将从这项研究中受益，因为这项研究改善了对神经状况的了解，并更好地证明了可能影响自己健康的化学效应。开发的模型将为化学效应分析提供更完整的系统，在减少测试中使用的脊椎动物数量方面具有巨大的潜力。

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）

Estrogen regulates development of the olfactory sensory system in the zebrafish embryo

雌激素调节斑马鱼胚胎嗅觉系统的发育

DOI：
发表时间：
2021
期刊：
E-life
影响因子：
0
作者：
Aya Takesono
通讯作者：
Aya Takesono

Zinc Oxide Nanoparticles Disrupt Development of Olfactory Sensory System Impairing Olfaction-Mediated Avoidance Behaviour in Zebrafish

氧化锌纳米颗粒扰乱嗅觉系统的发育，损害斑马鱼嗅觉介导的回避行为

DOI：
发表时间：
期刊：
PNAS
影响因子：
0
作者：
Aya Takesono
通讯作者：
Aya Takesono

Health Effects and Life Stage Sensitivities in Zebrafish Exposed to an Estrogenic Wastewater Treatment Works Effluent.

DOI：
10.3389/fendo.2021.666656
发表时间：
2021
期刊：
Frontiers in endocrinology
影响因子：
5.2
作者：
Cooper R;David A;Lange A;Tyler CR
通讯作者：
Tyler CR

Zebrafish as a Model for Fetal Alcohol Spectrum Disorders.

DOI：
10.3389/fphar.2021.721924
发表时间：
2021
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Alsakran A;Kudoh T
通讯作者：
Kudoh T

Early life exposure to ethinylestradiol enhances subsequent responses to environmental estrogens measured in a novel transgenic zebrafish.

DOI：
10.1038/s41598-018-20922-z
发表时间：
2018-02-09
期刊：
Scientific reports
影响因子：
4.6
作者：
Green JM;Lange A;Scott A;Trznadel M;Wai HA;Takesono A;Brown AR;Owen SF;Kudoh T;Tyler CR
通讯作者：
Tyler CR