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，脊髓肌萎缩(SMA)， 是由存活运动神经元基因SMN1突变引起的。SMN蛋白， 在SnRNP新陈代谢中起重要作用的基因，定位于 核质和细胞质。SMN的核分数积累 主要是在卡哈尔小体(CBS)内。卡哈尔小体是核细胞器 参与小核核糖核蛋白的生物发生。 值得注意的是，来自SMA患者的细胞明显减少 CBS的数量，以及之前对SMN基因敲除小鼠的研究表明 SMN缺乏核靶向性是SMA的生化缺陷。它是, 因此，开始解开CBS的功能至关重要，如果我们要 识别和了解SMN参与的细胞通路。 SMN蛋白与其他几种蛋白形成一个大的寡聚复合体， 统称为“双子座”。SMN复合体的每个成员 在CBS中积累，伴随着高浓度的SnRNPs。除了……之外 这种名为CBS的格曼蛋白高度富含一种名为p80 Colin的蛋白质。在……里面 为了进一步了解SNRNPs的生物发生及其在生物多样性中的作用 SMA的发病机制，我们有兴趣开发一种遗传模型系统来 研究卡哈尔的身体机能。这项提案的总体目标是执行 靶向破坏CB的Cajal小体的分子遗传学分析 小鼠体内的成分。这项建议的具体目标是：(1)分析表型 小鼠p80 Colin基因缺失对细胞和细胞的影响 生物水平；(2)探索SMN和SMN之间可能的遗传相互作用 Colin；(3)创造缺少SMN其他关键成员的基因敲除小鼠 复合体和(4)鉴定和鉴定与柯林相互作用的蛋白质。

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.