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The Fat4-Dchs1 pathway: A new regulator of neuronal development and migration

Fat4-Dchs1 通路：神经元发育和迁移的新调节因子

基本信息

批准号：
BB/M022544/1
负责人：
Philippa Francis-West
金额：
$ 61.24万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM022544%2F1
关键词：
Fat4 Dchs1 pathway new regulator

项目摘要

Development of the brain involves the generation of neurons (the major population of cells in the brain) and their migration to their final destination. After reaching their targets, neurons make the connections that will eventually "wire" the brain. This project will determine the role of two proteins called Fat4 and Dchs1 during brain development. Specifically, we will determine how these proteins regulate the generation and migration of newborn neurons. We already know that Fat4 and Dchs1 are essential for human brain development as mutations in Fat4 and Dchs1 in humans result in syndromes characterized by brain abnormalities and intellectual disability.The focus of this project will be on one region of the brain called the subventricular zone (SVZ), a thin tissue layer surrounding the walls of the lateral ventricle. This area represents the most prominent source of stem cells, which are able to generate new neurons both before and after birth. Abnormalities in SVZ neurogenesis are associated with cognitive decline, dementia and neurodegenerative diseases like Alzheimer's and Huntington's diseases. We will determine how Fat4 and Dchs1 control the generation of new neurons from the SVZ and their migration to their final destination. We will analyse how SVZ neural stem cell proliferation and differentiation are affected when Fat4 or Dchs1 are not present. We will also clarify why SVZ-derived neurons fail to migrate properly in the absence of Fat4 and Dchs1. We hypothesize that Fat4 and Dchs1 are required to ensure the proper directed collective movement of SVZ-derived neurons. To investigate this, we will use time-lapse imaging of neuronal migration in brain slice cultures and examine abnormalities in neuronal motility and directionality.We will also examine which signalling cascades are triggered by Fat4 and Dchs1 to control the generation and migration of new neurons in the mammalian brain. Our studies will identify crucial mechanisms in neural stem cell biology, which will not only help increase our understanding of brain development but also help design therapeutic strategies to repair the brain in trauma and disease.

大脑的发育涉及神经元（大脑中的主要细胞群）的产生及其迁移到最终目的地。到达目标后，神经元建立连接，最终将大脑连接起来。该项目将确定两种名为Fat4和Dchs1的蛋白质在大脑发育过程中的作用。具体来说，我们将确定这些蛋白质如何调节新生神经元的产生和迁移。我们已经知道Fat4和Dchs1对人类大脑发育至关重要，因为人类Fat4和Dchs1的突变会导致以大脑异常和智力残疾为特征的综合征。该项目的重点将放在大脑的一个区域，称为脑室下区（SVZ），这是一个围绕侧脑室壁的薄组织层。这个区域代表了干细胞的最主要来源，这些干细胞能够在出生前后产生新的神经元。SVZ神经发生的异常与认知能力下降、痴呆和神经退行性疾病如阿尔茨海默病和亨廷顿病有关。我们将确定Fat4和Dchs1如何控制SVZ新神经元的生成及其迁移到最终目的地。我们将分析当Fat4或Dchs1不存在时，SVZ神经干细胞增殖和分化是如何受到影响的。我们还将阐明为什么SVZ衍生的神经元在缺乏Fat4和Dchs1的情况下无法正常迁移。我们假设Fat4和Dchs1需要确保SVZ衍生神经元的正确定向集体运动。为了研究这一点，我们将在脑切片培养中使用神经元迁移的延时成像，并检查神经元运动性和方向性的异常。我们还将检查哪些信号级联被Fat4和Dchs1触发，以控制哺乳动物大脑中新神经元的产生和迁移。我们的研究将确定神经干细胞生物学中的关键机制，这不仅有助于增加我们对大脑发育的理解，还有助于设计治疗策略来修复创伤和疾病中的大脑。