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.
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