Coilin, Cajal Bodies and Spinal Muscular Atrophy

描述（由申请人提供）： 隐性致死性神经退行性疾病，脊髓性肌萎缩症（SMA）， 是由运动神经元生存基因SMN 1突变引起的。SMN蛋白， 在snRNP代谢中起重要作用，定位于 核质和细胞质。SMN的核部分积累 Cajal bodies（CB）。卡哈尔体是核细胞器 参与小核核糖核蛋白（snRNP）的生物发生。 值得注意的是，来自SMA患者的细胞显示出显著降低的细胞增殖。 CBs的数量，以及之前对Smn敲除小鼠的研究表明， SMN缺乏核靶向是SMA的生化缺陷。是的， 因此，如果我们要实现以下目标，就必须开始揭开CBs的功能 识别和理解SMN参与的细胞通路。 SMN蛋白与几种其他蛋白质形成大的寡聚复合物， 统称为“Gemins”。“SMN复合体的每个成员 在CB中积累，沿着高浓度的snRNP。除了 Gemin蛋白质CB高度富集称为p80卷曲蛋白的蛋白质。在 为了进一步深入了解snRNP的生物起源及其在生物学中的作用， SMA的发病机制，我们有兴趣开发一个遗传模型系统， 研究卡哈尔身体机能本提案的总体目标是执行一项 通过CB的靶向破坏进行Cajal体的分子遗传学分析 成分在小鼠体内。具体目的是：（1）测定表型 小鼠p80卷曲蛋白基因的缺失对细胞和 （2）探索SMN和SMN之间可能的遗传相互作用， coilin;（3）建立缺乏SMN其他关键成员的敲除小鼠 复合物和（4）鉴定和表征与卷曲蛋白相互作用的蛋白质。

DESCRIPTION (provided by applicant): The recessive-lethal neurodegenerative disorder, Spinal Muscular Atrophy (SMA), is caused by mutations in the Survival Motor Neurons gene, SMN1. SMN protein, which plays an important role in snRNP metabolism, is localized to both the nucleoplasm and the cytoplasm. The nuclear fraction of SMN accumulates predominantly within Cajal bodies (CBs). Cajal bodies are nuclear organelles involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs). Significantly, cells derived from SMA patients display markedly decreased numbers of CBs, and previous studies of Smn knockout mice have suggested that the lack of nuclear targeting of SMN is the biochemical defect in SMA. It is, therefore, critical to begin to unravel the functions of CBs if we are to identify and understand the cellular pathways in which SMN participates. SMN protein forms a large oligomeric complex with several other proteins, collectively called "Gemins." Each of the members of the SMN complex accumulates in CBs, along with high concentrations of snRNPs. In addition to the Gemin proteins, CBs are highly enriched in a protein called p80 coilin. In order to gain further insight into the biogenesis of snRNPs and its role in the pathogenesis of SMA, we are interested in developing a genetic model system to study Cajal body function. The overall goal of this proposal is to perform a molecular genetic analysis of Cajal bodies through targeted disruptions of CB components in mice. Specific Aims of this proposal are: (1) to assay phenotypic effects of a deletion in the mouse p80 coilin gene at both the cellular and organismal levels; (2) to explore possible genetic interactions between SMN and coilin; (3) to create knockout mice lacking other key members of the SMN complex and (4) to identify and characterize proteins that interact with coilin.