Support for synapses: the role of cell adhesion molecules in glial morphogenesis

支持突触：细胞粘附分子在神经胶质形态发生中的作用

• 批准号: BB/S010386/1
• 负责人: Ryan MacDonald
• 金额: $ 122.34万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS010386%2F1
• 关键词: Support; synapses; role; cell; adhesion

The central nervous system (CNS) consists of the brain, spinal cord and retina (eye). It controls most functions of the body and mind. Despite the importance of these tissues are made up of only two major cell types: neurons and glia. Most researchers focus on neurons because they are the electrical wires passing signals to perform daily functions. However, glial cells outnumber neurons in the CNS and they support neurons to make sure they are healthy and function properly. To make up the CNS, neurons and glia need to meet during development and make specific partnerships that last a lifetime. Glial cells have special shapes so that they can connect to the neurons. Changes in glial shape can make neurons sick and potentially lead to disease. So it is important to understand how glial cells get their shape in the first place so we can make sure they keep it and support the neurons throughout the lifespan. We don't know how glial cells get their shape and meet their neuronal partners. We also don't know exactly what happens to neurons if glial cells don't make these connections in the first place. I want to explore these really important fundamental questions.In order to really understand how glia get their shapes and support neurons the best way is to watch it happen in a living animal during their development. I am an expert in studying glial cells in the retina of the zebrafish using genetics and microscopy techniques. The retina is a really simple CNS tissue, if compared to the brain. I will use the zebrafish to study this very interesting problem as we can see inside it during early development, its retina has neurons and glia just like humans, and we can follow individual cells using fluorescent proteins. Thus, using microscopy I can watch how neurons and glia behave to meet and make their connections in a living fish. I have found that glia are active and change their shapes very quickly to find and contact specific neurons. We don't know what molecules are controlling the glia to find their neuronal partners. To identify molecules I carried out a genetic screen looking for glial cells with shape defects. This identified the cell adhesion molecules, which are important molecules for cell connections in many different tissues, including the retina and brain. However, we don't know how these particular ones work in the glia to control their shapes during development. To find out why these genes are important and how they help the glia find their partners I will delete them in zebrafish and observe how retina development goes wrong in animals without these genes. To achieve this I will use microscopy to watch glia and neurons in retinas that grow abnormally. Finally, I have shown before that if you don't have any glia in the zebrafish retina then it doesn't function properly. So I will test the vision of fish that still have glia but only their shapes, and connections to neurons, are affected. I will test this by using visual behavioral tests and stimulation with specific light patterns, these are experiments that can easily be done and something myself and other experts will work on together to accomplish.My research programme will tell us how glia find their partner neurons, which cell adhesion molecules are important for glia to get their shapes and how they make sure our CNS function normally. These answers will be very important for understanding how our retinas and brains are built in the first place. If we understand how glia shape is set up then maybe it will be the same molecules to maintain the connections, so this will also be very important for keeping each part of the CNS healthy as we age. Finally, these behaviors and molecules might help with discovering drugs and treatments to change glial shape and make sure they connect to neurons and support them again. This will be very important for patients with neurodegenerative diseases, like Alzheimers, or retina degeneration (major cause of blindness).

中枢神经系统(CNS)由大脑、脊髓和视网膜(眼)组成。它控制着身体和精神的大部分功能。尽管这些组织很重要，但它们只由两种主要细胞类型组成：神经元和胶质细胞。大多数研究人员将重点放在神经元上，因为它们是传递信号以执行日常功能的电线。然而，在中枢神经系统中，神经胶质细胞的数量超过了神经元，它们支持神经元，以确保它们健康和正常运作。为了组成中枢神经系统，神经元和胶质细胞需要在发育过程中相遇，并建立持续一生的特定伙伴关系。神经胶质细胞具有特殊的形状，因此它们可以连接到神经元。胶质细胞形状的变化会使神经元生病，并有可能导致疾病。因此，重要的是首先要了解神经胶质细胞是如何形成形状的，这样我们才能确保它们保持形状，并在整个生命周期内支持神经元。我们不知道神经胶质细胞是如何形成其形状并与它们的神经元伙伴相遇的。我们也不知道如果神经胶质细胞一开始就没有建立这些联系，神经元会发生什么。我想探索这些非常重要的基本问题。为了真正了解胶质细胞是如何形成形状并支持神经元的，最好的方法是观察活动物在发育过程中的情况。我是利用遗传学和显微镜技术研究斑马鱼视网膜神经胶质细胞的专家。如果与大脑相比，视网膜是一个非常简单的中枢神经系统组织。我将使用斑马鱼来研究这个非常有趣的问题，因为我们可以在斑马鱼的早期发育过程中看到它的内部，它的视网膜像人类一样有神经元和神经胶质细胞，我们可以使用荧光蛋白跟踪单个细胞。因此，使用显微镜，我可以观察神经元和神经胶质细胞如何在活着的鱼中相遇并建立联系。我发现，神经胶质细胞非常活跃，可以非常迅速地改变形状，以找到并联系特定的神经元。我们不知道是什么分子控制着神经胶质细胞寻找它们的神经元伙伴。为了识别分子，我进行了一项基因筛查，寻找有形状缺陷的神经胶质细胞。这确定了细胞黏附分子，这是许多不同组织中细胞连接的重要分子，包括视网膜和大脑。然而，我们不知道这些特殊的基因是如何在胶质细胞中工作的，在发育过程中控制它们的形状。为了找出为什么这些基因很重要，以及它们如何帮助神经胶质细胞找到伴侣，我将在斑马鱼中删除它们，并观察没有这些基因的动物的视网膜发育是如何出错的。为了实现这一点，我将使用显微镜观察视网膜中异常生长的胶质细胞和神经元。最后，我以前已经证明过，如果斑马鱼的视网膜中没有任何神经胶质细胞，那么它就不能正常工作。因此，我将测试仍有神经胶质的鱼的视力，但只有它们的形状和与神经元的连接受到影响。我将通过视觉行为测试和特定光模式的刺激来测试这一点，这些实验很容易完成，我自己和其他专家将共同努力完成。我的研究计划将告诉我们胶质细胞如何找到它们的伴侣神经元，哪些细胞黏附分子对胶质细胞形成形状很重要，以及它们如何确保我们的中枢神经系统正常功能。这些答案对于了解我们的视网膜和大脑最初是如何构建的非常重要。如果我们了解胶质细胞的形状是如何形成的，那么维持连接的分子可能是相同的，所以这对于随着年龄的增长保持中枢神经系统的每个部分的健康也是非常重要的。最后，这些行为和分子可能有助于发现改变神经胶质形状的药物和治疗方法，并确保它们与神经元连接并再次支持它们。这对于患有神经退行性疾病的患者非常重要，比如阿尔茨海默病或视网膜退化(失明的主要原因)。

项目成果

GliaMorph: a modular image analysis toolkit to quantify Müller glial cell morphology.

• DOI: 10.1242/dev.201008
• 发表时间: 2023-02-15
• 期刊: Development (Cambridge, England)

Unexpected opposing biological effect of genetic risk factors for Parkinson's disease

帕金森病遗传危险因素的意外相反生物学效应

• DOI: 10.1101/702340
• 发表时间: 2019
• 作者: Keatinge M

Glia Cell Morphology Analysis Using the Fiji GliaMorph Toolkit.

• DOI: 10.1002/cpz1.654
• 发表时间: 2023-01
• 期刊: Current protocols
• 作者: Kugler, Elisabeth;Breitenbach, Eva-Maria;MacDonald, Ryan
• 通讯作者: MacDonald, Ryan

GliaMorph: A modular image analysis toolkit to quantify Müller glial cell morphology

GliaMorph：量化 Müller 胶质细胞形态的模块化图像分析工具包

• DOI: 10.1101/2022.05.05.490765
• 发表时间: 2022
• 作者: Kugler E

Müller Glia maintain their regenerative potential despite degeneration in the aged zebrafish retina.

• DOI: 10.1111/acel.13597
• 发表时间: 2022-04
• 期刊: Aging cell
• 影响因子: 7.8