Molecular regulation of human callosal development

人类胼胝体发育的分子调控

• 批准号: 6601723
• 负责人: Linda J Richards
• 金额: $ 20.87万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6601723
• 关键词: axon; corpus callosums; developmental neurobiology; gene expression; glia; human fetus tissue; in situ hybridization; laboratory mouse; neurogenesis; northern blottings; protein structure function

DESCRIPTION (provided by applicant): Although over 50 human congenital syndromes are associated with agenesis of the corpus callosum (ACC), we know very little about why ACC actually occurs in developing human fetuses. Part of the reason for this is that we lack fundamental knowledge about the molecular and developmental requirements for normal callosal formation in humans. In mice we have made significant progress in understanding how the corpus callosum forms. My laboratory has identified several midline glial structures that regulate callosal axon pathfinding as well as some of the genes that are expressed by these structures. We have also been analyzing a number of different mouse mutant strains that phenotypically display ACC and have determined that these genes may play specific and vital roles in callosal formation. This proposal is specifically designed to move our scientific knowledge base in animal models to humans. Using this mechanism of "Exploratory grants in pediatric brain disorders: Integrating the science" we have built a team of professionals with basic science and clinical expertise in midline brain development. Data from experiments described here will form the basis of a fundamental infrastructure of knowledge between the laboratory and clinical settings. This approach is essential to moving this field forward toward an understanding of the basis and treatment of ACC. In aim 1 we determine if midline glial populations and the chemorepellent molecule Slit2, that are required for callosal formation in mice, are present (and therefore possibly act in an analogous way) in human fetal brains. In aim 2 we investigate the expression of a number of genes that cause ACC in mouse to determine if they are expressed at developmentally relevant times and locations in human fetal tissue. This data will enable us to evaluate the potential of these genes as candidates that may be mutated in human cases of ACC. Finally we examine the development of a structure called the commissural plate, that may underlie the formation of all forebrain midline commissures. The commissural plate has been described in human development but it is not known whether its proper formation is required for commissure formation and whether it expresses guidance factors for commissural axons. In aim 3 we address these issues by first analyzing the formation of the commissural plate in human fetal brains using diffusion tensor imaging and then address whether the same structures form in mice where we can more easily study its development. These experiments are the first to address the molecular and genetic basis of ACC in humans and are based on extensive work in mice. Our goal is to determine how ACC occurs in humans and what factors are common amongst the numerous congenital syndromes in which ACC and other commissural defects occur.

描述（由申请人提供）： 尽管超过50种人类先天性综合症与胼胝体（ACC）发育不全有关，但我们对ACC实际上发生在发育中的人类胎儿中的原因知之甚少。部分原因是我们缺乏关于人类正常胼胝体形成的分子和发育要求的基本知识。在小鼠中，我们在理解胼胝体如何形成方面取得了重大进展。我的实验室已经确定了几个中线神经胶质结构，调节胼胝体轴突寻路以及一些基因，这些结构表达。我们还分析了一些不同的小鼠突变株，表型显示ACC，并确定这些基因可能在胼胝体形成中发挥特定的和重要的作用。这项提议是专门设计来将我们在动物模型中的科学知识基础转移到人类身上的。利用“儿科脑疾病探索性赠款：整合科学”的机制，我们建立了一支在中线脑发育方面具有基础科学和临床专业知识的专业团队。来自这里描述的实验的数据将形成实验室和临床环境之间的基本知识基础设施的基础。这种方法是必不可少的，以推动这一领域向前了解的基础和处理ACC。 在目标1中，我们确定在小鼠中胼胝体形成所需的中线胶质细胞群体和化学排斥分子Slit2是否存在于人类胎儿大脑中（因此可能以类似的方式起作用）。在目标2中，我们研究了导致小鼠ACC的许多基因的表达，以确定它们是否在人类胎儿组织中在发育相关的时间和位置表达。这些数据将使我们能够评估这些基因作为候选人的潜力，可能会在人类ACC.Finally突变的情况下，我们研究的发展称为连合板的结构，这可能是形成所有前脑中线连合。连合板在人类发育中已有描述，但尚不清楚连合板的正确形成是否是连合形成所必需的，以及它是否表达连合轴突的指导因子。在目标3中，我们首先使用扩散张量成像分析人类胎儿大脑中连合板的形成，然后讨论是否在小鼠中形成相同的结构，这样我们可以更容易地研究其发育。这些实验是第一个解决人类ACC的分子和遗传基础的实验，并且是基于在小鼠中的广泛工作。我们的目标是确定ACC如何在人类中发生，以及在ACC和其他连合缺陷发生的众多先天性综合征中，哪些因素是共同的。