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.
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