Small ribonucleoproteins (RNPs) are essential components of all cells. Eukaryotic gene expression requires a constellation of small non-coding RNP particles that participate in multiple aspects of organismal function. The long-term goal of this proposal is to understand the molecular mechanisms that govern the biogenesis, subcellular localization and function of these RNPs. As key elements of the spliceosome, the Sm-class small nuclear (sn)RNPs are essential for pre-messenger RNA splicing. Assembly into stable RNP particles is thought to be mediated by the Survival Motor Neuron (SMN) protein complex, which loads Sm proteins onto snRNAs, forming a heptameric ring structure called the Sm-core. Understanding this process is important for human health, as mutations in the SMN1 gene cause a genetic disease called Spinal Muscular Atrophy (SMA). In addition to their fundamental role in the biology of all eukaryotic cells, recent findings show that Sm proteins also play an important role in the specification of primordial germ cells. Because the germline is the only metazoan cell lineage that transmits the genetic information to subsequent generations, understanding the molecular mechanisms that are used make this important cell fate decision remains a central challenge to developmental biology. In fact, the assembly and transport of RNPs to remote cellular locations has emerged as a key feature in setting up the cellular asymmetries that are required for a wide variety of cell fate determinations. Thus a detailed understanding of RNP biogenesis is essential not only to the study of RNA splicing, but is also important for germ cell development. To gain insight into these processes, we have developed genetic model systems in Drosophila.
Specific Aims of this proposal are to: (1) ascertain the functions of Sm proteins in germ cell development (2) identify and characterize novel RNAs that associate with Sm proteins, and (3) investigate the dynamics and mechanics of Sm protein and snRNA transport in vivo. The combined data will elucidate the mechanisms of RNP biogenesis at the molecular, cellular and developmental biological levels.
Cellular asymmetries are created and maintained by a process that includes the transport, localization and expression of ribonucleoproteins (RNPs) at distinct, and often far-flung, regions of a cell. Such asymmetries are important in diverse cell types, from neurons to germ cells, and failures in RNP transport have been implicated in neurodegeneration and infertility. Thus a detailed understanding of RNP biogenesis is crucial to harnessing the tremendous biomedical research potential of RNPs, as both tools and targets.
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