Role of Kdm5c dosage in mouse neural development

项目摘要/摘要 具有额外X染色体的个体，如Klinefelter综合征(XXY)或Triple X 综合征(XXX)通常有先天性异常，包括神经功能减退。他的存在 X染色体额外拷贝的产生导致了逃脱X失活的额外基因拷贝。因此，反常的 高剂量的逃逸基因是常见表型致病的诱人靶点 额外的X综合征。KDM5C是逃脱X失活的基因之一，它代表着一种特殊的 有吸引力的候选者，因为它是对启动子和增强子非常重要的剂量敏感的主调控因子 调节和神经功能。事实上，基因缺失或复制的患者具有智力 残疾。 为了解决Kdm5c在表达上的作用，我们将使用一个独特的X倾斜失活的小鼠模型 以及由于插入一个额外的基因拷贝而精确地过表达Kdm5c。其他动物模型 Klinefelter或Triple X综合征已有报道，但无法确定其疗效 在这种模型中增加特定逃逸基因的剂量，因为整个逃逸基因队列是 过度表达。 在多发X综合征中观察到的神经学表型可能源于发育 胚胎发育过程中的缺陷。因此，要确定Kdm5c过度表达对通路的影响至关重要 对于神经发生，我们使用了一种新的小鼠模型，该模型特异性地过表达Kdm5c并在体内进行监测 在神经发育的关键时间点，全基因组的遗传和表观遗传变化与 胚胎中的神经发生。基因表达变化和表观遗传变化将结合起来识别和 定位Kdm5c过表达对基因和调控元件的影响。 我们的目标是确定基因表达和表观遗传修饰是否在 Kdm5c过度表达的胚胎中的神经发育。我们全面的活体方法将 为理解逃逸基因剂量在相关神经表型中的作用提供新的见解 表现为常见的X染色体非整倍体综合征。

Project Summary/Abstract Individuals with a supernumerary X chromosome such as those with Klinefelter syndrome (XXY) or Triple X syndrome (XXX) often have congenital abnormalities that include reduced neurological function. The presence of extra copies of the X chromosome results in extra copies of genes that escape X inactivation. Thus, abnormally high dosage of escape genes is an attractive target for the causation of phenotypes seen in common supernumerary X syndromes. KDM5C, one of the genes that escapes X inactivation, represents a particularly attractive candidate because it is a dosage-sensitive master regulator important for promoter and enhancer regulation and neurological function. Indeed, patients with deletion or duplication of the gene have intellectual disability. To address the role of Kdm5c over expression we will employ a unique mouse model with skewed X inactivation and precise over expression of Kdm5c due to insertion of one extra copy of the gene. Other animal models of Klinefelter or Triple X syndromes have been reported, however it is impossible to determine the effects of increased dosage of a particular escape gene in such models since the entire cohort of escape genes is overexpressed. It is probable that neurological phenotypes observed in supernumerary X syndromes stem from developmental defects during embryogenesis. Thus, to determine the effects of Kdm5c over expression on the pathways critical for neurogenesis we use a novel mouse model which specifically over expresses Kdm5c and monitor in vivo genetic and epigenetic changes genome-wide during neural development at critical time points associated with neurogenesis in the embryo. Gene expression changes and epigenetic changes will be integrated to identify and map genes and controlling elements affected by over expression of Kdm5c. Our goals are to determine whether gene expression and epigenetic modifications are dysregulated during neurodevelopment in embryos where Kdm5c is over expressed. Our comprehensive in vivo approaches will provide new insights in understanding the role of escape gene dosage in relevant neurological phenotypes manifested in common X chromosome aneuploidy syndromes.