Simmonds, Andrew - University of Alberta - Department of Cell Biology

研究领域

Our research group uses a combination of live-cell imaging, Drosophila genetics, cell-culture and molecular biology to study post-transcriptional gene regulation of critical cellular processes like mitosis and cell differentiation. Specifically we study the formation, transport and function of cytoplasmic mRNA processing-bodies (P-bodies), a newly identified cellular component that is thought to be part of the RNA interference pathway. These RNA-protein complexes seem to play key roles in regulating mRNA transport, localization and storage within the cell. A second group within our laboratory studies several proteins that regulate the differentiation of muscle cells, in particular those cells that form the early heart tube. Regulation of the transport, translation and degradation of cytoplasmic messenger RNAs in the developing embryo. In eukaryotic cells, cytoplasmic processing (P-) bodies regulate directly regulate mRNAs. In mammalian cells, a core component of P-bodies is the GW182 family of proteins. The GW182 protein family has been linked to microRNA and small interfering RNA gene regulation. Our group was the first to identify and functionally confirm that there is only a single GW182-like protein (we have named Gw) in the genetic model system Drosophila melanogaster. Using a combination of cultured cells as well as studies in whole animals, we are attempting to dissect the cellular roles and cytoplasmic events that regulate mRNAs including the role of Gw-containing P-bodies. There is a long history of using Drosophila to establish the basic pathways of gene regulation, and in most cases, this information can be translated directly to mammalian cells (humans). The advantages of using a model system have already helped us to determine that loss of Gw function leads to uncoordinated nuclear (chromosome) divisions. Using the wealth of genetic and biochemical tools that have been developed specifically for working with Drosophila, we will address three main questions: 1) What is the role of cytoplasmic Gw during the post-transcriptional regulation of messenger RNAs? 2) Why is a mainly cytoplasmic protein like Gw required for successful chromosome division? 3) How is the production of Gw protein and formation of cytoplasmic GW-containing P-bodies regulated? With increased understanding of how this protein functions within the cell and how it, in turn, is regulated, our research will help with diagnosis and treatment of several poorly understood diseases that have been linked to GW182 in humans. Determining the protein complex required for transport, storage and regulation of the mRNA product of the wnt-1 oncogene. An ongoing project in the lab is the characterization of the proteins that are required for mRNA localization of transcripts encoded by oncogenes of the wnt family. For example, in polarized epithelial cells, the wnt-1 mRNA does not localize to the endoplasmic reticulum in the majority of the cytoplasm, instead moving to a very small region just under the apical cell membrane. This transport requires multiple sequences within the 3’ untranslated region (UTR) of the transcript. Using a novel method of RNA affinity chromatography, we have identified several potential trans-acting proteins that bind the wnt-1 3’UTR. The genes encoding these proteins are being cloned and tested both biochemically and in living cells to determine their role in the cellular machinery that traffic cytoplasmic mRNAs. Regulation of muscle cell specification by a Sd/Vg/Dmef2 complex Approximately one percent of newborn infants manifest congenital heart malformation due to inherited mutations in one or more genes required for proper heart formation. We study two proteins (Sd/TEF-1 and Mef-2) that have critical roles in establishing a heart cell fate. There are multiple members of the human Sd/Tef-1 and Mef-2 protein families and it has been extremely difficult to identify co-factors that regulate their activity. However in Drosophila melanogaster, there is only a single Sd/Tef-1 and Mef-2 protein family member required during heart formation. We have identified several potential novel co-factors and we are currently testing their role in heart formation including activation of micro-RNA expression.

近期论文

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Li, J., Najand, N., Long, W. and Simmonds A.J. (2010) “Imaging the Cellular Dynamics of Drosophila Argonaute proteins” Methods in Molecular Biology (in press) Schneider, M.D., Bains, A.K , Rajendra, T.K., Domiski, Z., Matera, A.G, and Simmonds A.J. (2010) “Characterization of the Drosophila MRP (mitochondrial RNA processing) RNA” RNA (in press) Deng, H., Bell J.B. and Simmonds A.J. (2010) “Vestigial is required during late-stage muscle differentiation in Drosophila melanogaster embryos”. Molecular Biology of the Cell (in press) Foley E., Harris, H. Hughes, S.C. and Simmonds A.J. (2009) “I CanFly, Can You? – Meeting Report –The 10th Canadian Drosophila Research Conference” Fly 3(4) 298-299. Deng, H., Hughes S.C., Bell J.B. and Simmonds A.J. (2009) “Vestigial, Scalloped and Dmef2 form alternative transcriptional complexes during muscle differentiation in Drosophila melanogaster” Molecular Biology of the Cell Jan;20(1):256-69. dos Santos, G., A. J. Simmonds and H. M. Krause (2008). "A stem-loop structure in the wingless transcript defines a consensus motif for apical RNA transport." Development 135(1): 133-43. Najand, N. and A. J. Simmonds (2007). "A minimal WLE2 element is not sufficient to direct apical localization in the absence of RNAs containing the full length wingless 3'UTR." RNA Biology 4(3): 138-46. Nelson, M. R., H. Luo, H. K. Vari, B. J. Cox, A. J. Simmonds, H. M. Krause, H. D. Lipshitz and C. A. Smibert (2007). "A multiprotein complex that mediates translational enhancement in Drosophila." Journal of Biological Chemistry 282(47): 34031-8. Schneider, M. D., N. Najand, S. Chaker, J. M. Pare, J. Haskins, S. C. Hughes, T. C. Hobman, J. Locke and A. J. Simmonds (2006). "Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development." Journal of Cell Biology 174(3): 349-58.