Molecular regulation of human callosal development

描述(由申请人提供)： 尽管有超过50种人类先天综合征与胼胝体发育不全(ACC)有关，但我们对为什么ACC实际上发生在发育中的人类胎儿中知之甚少。造成这种情况的部分原因是，我们缺乏对人类正常的膝盖骨形成所需的分子和发育要求的基础知识。在小鼠身上，我们已经在了解老茧是如何形成的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，它们调控着胼胝体轴突的寻路，以及这些结构表达的一些基因。我们还分析了一些不同的小鼠突变株，这些突变株表现出ACC的表型，并确定这些基因可能在膝盖骨形成中发挥特定和重要的作用。这项建议是专门为将我们在动物模型中的科学知识库转移到人类而设计的。利用这种“儿童脑疾病探索性资助：整合科学”的机制，我们已经建立了一支在中线脑开发方面具有基础科学和临床专业知识的专业团队。这里描述的实验数据将构成实验室和临床环境之间基本知识基础结构的基础。这种方法对于推动这一领域向前发展，以了解ACC的基础和治疗是至关重要的。 在目标1中，我们确定在人类胚胎大脑中是否存在(因此可能以类似的方式起作用)小鼠的膝盖骨形成所需的中线神经胶质细胞群和化学排斥性分子Slit2。在目标2中，我们研究了一些引起小鼠ACC的基因的表达，以确定它们是否在发育相关的时间和位置在人类胎儿组织中表达。这些数据将使我们能够评估这些基因作为可能在人类ACC病例中突变的候选基因的潜力。最后，我们研究了一种叫做连合板的结构的发育，它可能是所有前脑中线连合形成的基础。连合板在人类发育过程中已经被描述过，但尚不清楚连合的形成是否需要它的正确形成，以及它是否表达了连合轴突的指导因素。在目标3中，我们首先使用扩散张量成像技术分析人类胎儿大脑中连合板的形成，然后解决在小鼠身上是否形成相同的结构，以便我们更容易地研究其发育。这些实验是第一次解决人类ACC的分子和遗传基础，并基于对小鼠的广泛研究。我们的目标是确定ACC在人类中是如何发生的，以及在众多发生ACC和其他连合缺陷的先天性综合征中，哪些因素是共同的。

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.