Role of Kdm5c dosage in mouse neural development

项目总结/摘要 具有额外X染色体的个体，如Klinefelter综合征（XXY）或三重X 综合征（XXX）通常具有先天性异常，包括神经功能降低。存在 X染色体的额外拷贝导致逃避X失活的基因的额外拷贝。因此， 高剂量的逃逸基因是一个有吸引力的目标的原因表型常见的 多余X综合征KDM 5C是逃避X失活的基因之一，代表了一个特别重要的基因。 有吸引力的候选物，因为它是对启动子和增强子重要的剂量敏感的主调节剂 调节和神经功能。事实上，该基因缺失或重复的患者具有智力 残疾。 为了解决Kdm 5c过度表达的作用，我们将采用一种具有偏斜X失活的独特小鼠模型 以及由于插入了一个额外拷贝的基因而导致的Kdm 5c的精确过表达。其他动物模型 Klinefelter综合征或三X综合征已有报道，但不可能确定 在这样的模型中增加特定逃逸基因的剂量，因为整个逃逸基因组是 过度表达 在额外X综合征中观察到的神经系统表型可能源于发育 胚胎发育过程中的缺陷。因此，为了确定Kdm 5c过表达对关键通路的影响， 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Kdm 5c并在体内监测 在神经发育过程中的关键时间点， 胚胎中的神经发生基因表达变化和表观遗传变化将被整合，以识别和 定位受Kdm 5c过表达影响的基因和控制元件。 我们的目标是确定基因表达和表观遗传修饰是否失调， 在Kdm 5c过度表达的胚胎中的神经发育。我们全面的体内方法将 为理解逃逸基因剂量在相关神经表型中的作用提供了新的见解 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.