Spinal Muscular Atrophy (SMA) is a recessive neurogenetic disorder, caused by mutation of the human survival of motor neurons 1 (SMN1) gene. Patients with SMA typically die early in childhood. SMN protein is part of a large, oligomeric complex that plays an essential role in small nuclear ribonucleoprotein (snRNP) assembly. These small RNPs are required for pre-messenger RNA splicing, a process central to all eukaryotic cells. Small RNP biogenesis is compromised in patient cells, although the underlying cause of the SMA phenotype is not yet known. Thus learning more about SMN's role in the metabolism of snRNPs is essential not only to the study of RNA processing, but is important for our understanding of this devastating neuromuscular disease. Small RNP biogenesis is a stepwise process, taking place in multiple subcellular compartments. In mammalian cells, the SMN complex localizes to the nucleus and the cytoplasm. Whereas SMN is diffusely distributed throughout the cytosol, the nuclear fraction of the protein accumulates in Cajal bodies, colocalizing with an SMN-interacting protein called coilin. Cajal bodies are nuclear suborganelles involved in the maturation of snRNPs. The long-term goal of this proposal is to understand the molecular mechanisms that govern the biogenesis and subcellular localization of snRNPs. In other words, we seek to know how snRNPs are packaged, transported and delivered to their sites of action in the nucleus. In order to gain further insight into the biogenesis of snRNPs and its role in the pathogenesis of SMA, we have developed transgenic mouse and cell culture model systems to study SMN and Cajal bodies.
Specific Aims of this proposal are: (1) to determine the function of the SMN complex in the import of small nuclear RNPs, (2) to identify factors required for SMN and snRNP assembly and import, and (3) to characterize the role of the SMN-coilin interaction at the organismal level. ? ?
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