The role of capicua in spinocerebellar ataxia type 1

描述(申请人提供)：本项目的目标是确定Capicua(CIC)在脊髓小脑性共济失调1型(SCA1)中的作用，SCA1是一种由Aaxin-1(ATX-1)中的多谷氨酰胺扩张引起的神经退行性疾病。CIC是果蝇中的一种转录抑制因子，初步结果表明，CIC与ATX-1相互作用，共定位于SCA1中变性的浦肯野神经元，在ATX-1基因缺失的小鼠中其水平降低。我将首先分析CIC在野生型和ATX-1基因缺失小鼠发育过程中的表达。我将建立并鉴定CIC缺失小鼠(CIC-/-)，以确定CIC在体内的正常作用，并确定其在ATX-1正常功能中的作用(当与ATX-1缺失小鼠杂交时)。CIC缺失的小鼠将与SCA1基因敲入模型杂交，以确定CIC是否以及如何影响SCA1的发病机制。鉴于CIC作为转录抑制因子的作用，我将通过微阵列分析来研究CIC和CIC-/-小鼠的基因表达变化。CIC突变的变化将与ATX-1缺失和SCA1敲除小鼠(目前由其他实验室成员进行)进行比较，以确定那些与SCA1和ATX-1功能最相关的变化。该项目将确定CIC在哺乳动物中的作用，以及在ATX-1的正常功能和SCA1发病中的作用。

DESCRIPTION (provided by applicant): The goal of this project is to determine the role of capicua (Cic) in spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease caused by a polyglutamine expansion in Ataxin-1 (Atx-1). Cic is a transcriptional represser in Drosophila and preliminary results show that Cic interacts with Atx-1, co-localizes to Purkinje neurons that degenerate in SCA1, and its level is reduced in Atx-1-null mice. I will first analyze the expression of Cic during development in wild-type and Atx-1-null mice. I will generate and characterize Cic- null mice (Cic-/-) to determine the normal role of Cic in vivo and to determine its role in the normal function of Atx-1 (when crossed to Atx-1-null mice). Cic-null mice will be crossed to a knock-in model of SCA1 to determine whether and how Cic affects SCA1 pathogenesis. Given Cic's role as a transcriptional represser, I will investigate gene expression changes by microarray analysis in Cic and Cic-/- mice. Changes in Cic mutants will be compared to those of Atx-1-null and SCA1 knock-in mice (currently being performed by other laboratory members) to pinpoint those changes most relevant to SCA1 and Atx-1 function. This project will establish the role of Cic in mammals and in the normal function of Atx-1 and in SCA1 pathogenesis.