Characterization of Gli3 function during development of the corpus callosum: a model for the pathogenesis of ACS and GCPS Syndrome

智力迟钝（MR）是一种相对常见的认知障碍形式，影响了1%- 3%的人口。MR疾病的异常异质性使理解MR的生物学变得复杂。肢端胼胝体综合征（Acrocallosal syndrome， ACS）是一种特殊形式的MR，其特征是胼胝体缺失，胼胝体是连接大脑左右半球的主要纤维束。此外，Greig头多指综合征（GCPS）的一部分患者智力迟钝，这两种综合征都可能由锌指转录因子基因GLI3突变引起。我的实验室主要研究Gli3在大脑皮层发育过程中的作用。在这项提议中，我们想用Gli3突变小鼠作为模型来阐明导致这些动物和ACS/GCPS患者胼胝体缺失的机制。我们将使用Dil示踪技术来检查皮质神经元的轴突投影，并使用原位杂交和免疫组织化学分析来确定胼胝体发育的分子和细胞基础。从这一分析，我们期望进一步的线索，我们的理解背后的原因，这是最终需要确定磁共振患者的潜在治疗方法。

Mental Retardation (MR) is a relatively common form of cognitive impairment affecting 1%- 3% of the population. Understanding the biology of MR is complicated by the extraordinary heterogeneity of MR disorders. Acrocallosal syndrome (ACS) represenst a specific form of MR which is characterized by the absence of the corpus callosum, the mafor fiber tract connecting the left and right cerebral hemisphere. Also, a subset of Greig cephalopolydactyly syndrome (GCPS) patients are mentally retarded and both syndromes can be caused by mutations in the zinc finger transcription factor gene GLI3.My lab has a major interest in characterizing the role of Gli3 during development of the cerebral cortex. In this proposal we want to use Gli3 mutant mice as a model to elucidate the mechanisms leading to the absence of the corpus callosum in these animals and by interference in ACS/GCPS patients. We will use Dil tracing techniques to examine axonal projections of cortical neurons and in situ hybrdization and immunohistochemical analysis to define the molecular and cellular basis for the agenesis of the corpus callosum. From this analysis we expect further clues to our understanding of the causes underlying MR which is ultimatively required for defining potential treatments of MR patients.