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Return to: College of Biological Sciences: Medical School: U of M Home |
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Areas of Research Strength: Cytoskeleton and cell motility Developmental mechanisms back to top |
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Research Techniques: protein biochemistry molecular genetics (e.g., transgenic organisms) classical genetics (e.g., isolation of mutations) molecular cytology; confocal and conventional light microscopy back to top |
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Research Interests: Microtubules provide the architectural framework on which many cellular organelles and molecules are transported within the cytoplasm. At a basic level the regulation of microtubule-based transport within cells is dependent on the cytoplasmic motor proteins (dyneins and kinesins) that translocate along the microtubule lattice. These unidirectional motors, in combination with the assembly of polarized arrays of microtubules within cells, provide a mechanism to partition cellular organelles and molecules within a cell's cytoplasmic compartment. Malfunctions in motor function influence global aspects of cell biology including the establishment of cell polarities, the maintenance of genomic stability, and cell-cell communicationan underlie a growing list of medical maladies including cancer and birth defects. The Hays’ laboratory is applying genetic, molecular and biochemical approaches in Drosophila to study the function and regulation of cytoplasmic dynein. Diversification of dynein function: Cytoplasmic dynein contains a homodimer of the motor subunit that generates force against the microtubule substrate. In addition, a complex of accessory subunits at the base of the motor subunit is thought to mediate the attachment of dynein to a variety of cellular cargoes. In one line of investigation, the lab is testing the hypothesis that the subunits within the multi-protein motor complex are specialized in their functions. If different subunits act in different processes, then the phenotypes associated with mutations in each subunit may differ. The phenotypes associated with mutations in each subunit are being characterized using living cell microscopy and biochemical approaches. The efforts will help to understand how cytoplasmic dynein accomplishes multiple tasks. On a genomic scale, modifier screens have identified candidate genes that may reveal novel dynein functions and regulatory pathways. For example, the gene encoding a cytoplasmic transmembrane protein involved in EGFR signaling has been identified as a modifier of dynaction function. Defects in vesicle trafficking through the secretory or endosomal pathways may impact EGFR signaling. Understanding the mechanistic basis for the genetic interactions between identified modifier loci and the dynein pathway remains an important goal for the laboratory. Mitotic functions for dynein: The lab's previous mutational analysis of the dynein heavy chain subunit in Drosophila showed that the motor is essential for zygotic development and cell viability. We extended these analyses to characterize dynein function in the syncytial mitotic divisions of living embryos. These studies show that dynein function is required for multiple mitotic functions including centrosome migration along the nuclear envelope and the attachment of centrosomes to the poles of mitotic spindles. In more recent work, the lab is examining the role for dynein in chromosome attachment and cell cycle checkpoint controls. Dynein and dynactin accumulate rapidly on prometaphase kinetochores and subsequently move off kinetochores towards the poles during late prometaphase. Our work suggests that dynein transports checkpoint proteins off the attached kinetochores and may serve to "shut off" the metaphase checkpoint prior to anaphase. Developmental functions for dynein: During animal development the specification of cell fate is often preceded by an asymmetric cell division. Spindle orientation controls the plane of cell division and so determines how cytoplasmic constituents are partitioned to daughter cells. In Drosophila, asymmetric division gives rise to a single oocyte within a 16-cell cyst. Using mutations in the Drosophila dynein heavy chain, shows that cytoplasmic dynein is required for the asymmetric cell divisions that give rise to the oocyte. The loss of dynein function results in the failure to specify an oocyte. The Hay's lab is further investigating the hypothesis that dynein and other motor proteins are utilized in the intracellular transport of morphogens required for proper maturation of the egg. back to top |
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Selected Publications: Iyadurai, S., Robinson, J.T., Ma, L., Mische, S., Li, M-G., Brown, W., Guichard, A., Bier, E. and T.S. Hays. (2008). The interaction of Dynein and Star in EGFR signaling and ligand trafficking ( J. Cell Sci., in press). Boylan KL, Mische S, Li M, Marques G, Morin X, Chia W, Hays TS. 2008. Motility screen identifies Drosophila IGF-II mRNA-binding protein, a Zipcode-Binding Protein acting in oogenesis and synaptogenesis. PLoS 4:e36 Li, Z, Wang L, Hays TS, Cai Y. 2008. Dynein-mediated apical localization of crumbs transcripts is required for Crumbs activity in epithelial polarity. J. Cell Biol. 180:31-8. Riggs, B., Fasulo, B., Royou, A., Mische, S., Cao, J., Hays, T.S. and W. Sullivan. 2007. The concentration of Nuf, a Rab11 effector, at the MTOC is cell cycle regulated, Dynein-dependent and coincides with the timing of furrow formation in the early Drosophila embryo. Mol. Biol. Cell, 18:3312-22. Mische, S., M-G. Li., M. Serr, T.S. Hays. 2007. Direct observation of regulated RNP transport across the nurse cell/ oocyte boundary. Mol. Biol. Cell. 18, 224. Song, Y. Benison G, Nyarko A, Hays TS, Barbar E. 2007. Potential role for phosphorylation in differential regulation of the assembly of dynein light chains. J. Biol. Chem., 282: 17272-9. Talbott M, Hare M, Nyarko A, Hays TS, Barbar E. 2006. Folding is coupled to dimerization of Tctex-1 dynein light chain. Biochemistry. 2006 Jun 6;45(22):6793-800 Pfister KK, Fisher EM, Gibbons IR, Hays TS, Holzbaur EL, McIntosh JR, Porter, ME, Schroer TA, Vaughan KT, Witman GB, King SM, Vallee RB. 2005. Cytoplasmic dynein nomenclature. J. Cell Biol. 171:411-3. Siller KH, Serr M, Steward R, Hays TS, Doe CQ. 2005. Live Imaging of Drosophila Brain Neuroblasts Reveals a role for Lis1/Dynactin in Spindle Assembly and Mitotic Checkpoint Control. Mol Biol Cell. 16: 5127-40. Papoulas, O, Hays, TS, Sisson, JC. 2005. The golgin Lava lamp mediates dynein-based Golgi movements during Drosophila cellularization. Nat Cell Biol. 7(6): 612-8. Nyarko, A., Hare, M., Hays, T.S. and Barbar, E. (2004) The intermediate chain of cytoplasmic dynein is partially disordered and gains structure upon binding to light-chain LC8. Biochemistry 43:15595-15603. Wang, L., Hare, M., Hays, T.S., Barbar, E. (2004) Dynein light chain LC8 promotes assembly of the coiled-coil domain of swallow protein. Biochemistry 43(15):4611-4620. Li, M.-G., Serr, M., Newman, E.A. and Hays, T.S. (2003) The Drosophila tctex-1 light chain is dispensible for essential cytoplasmic dynein functions, but is required during spermatid differentiation. Mol. Biol. Cell. v. 15:3005-14. Riggs, B., Rothwell, W. Mische*, S., Debec, A., Hickson, G., Matheson, J., Gould, G., Hays*, T.S. and Sullivan, W. (2003) Actin cytoskeleton remodeling during metaphase and cellular furrow formation requires recycling endosomal components Nuclear-fallout and Rab11. Journal Cell Biology 163:143-154. Basto, R., Scaerou, F., Wojcik*, E., Gomes, R., Hays*, T. and Karess, R. (2003) In vivo dynamics of the Rough Deal checkpoint protein during Drosophila mitosis. Current Biology 14:56-61. Silvanovich, A., Li, M.-G., Serr, M., Mische, S. and Hays, T.S. (2003) The third P-loop domain in cytoplasmic dynein heavy chain is essential for dynein motor function and ATP-sensitive microtubule binding. Mol. Biol. Cell. 14:1355-1365. Boylan, K. and Hays, T.S. (2002) The gene for the intermediate chain subunit of cytoplasmic dynein is essential in Drosophila. Genetics 162:1211-1220. Makokha, M., Hare, M., Li, M.-G., Hays, T.S. and Barbar, E. (2002) Interactions of Cytoplasmic Dynein Light Chains Tctex-1 and LC8 with the Intermediate Chain IC74. Biochemistry 41(13):4302-1. Wojcik, E., Basto, R., Serr, M., Scareou, F., Karess, R. and Hays, T. S.. (2001) Kinetochore dynein: It’s dynamics and role in the transport of the rough deal checkpoint protein. Nature Cell Biology 3(11):1001-1007. Hays, T.S. and Li, M.-G. (2001) Kinesin Transport: Driving kinesin in the neuron. Curr. Biol.11:R136-139. Barbar, E., Kleinman, B., Imhoff, D., Li, M.-G., Hays, T.S. and Hare, M. (2001) A highly conserved light chain of cytoplasmic dynein, LC8: Dimerization and folding. Biochemistry 40:1596-1605. Wojcik, E. and T.S. Hays (2000) The SCF ubiquitin ligase protein slimb regulates centrosome duplication in Drosophila. Curr. Biol. 10:1131-1134. King, J., Hays, T.S. and Nicklas, R.B. (2000) Dynein is a transient kinetochore component whose binding is regulated by microtubule attachment, not tension. J. Cell Biol. 13 151(4):739-748. Hays, T.S. and Karess, R. (2000) Swallowing dynein: a missing link in RNA localization? Nature Cell Biol. 2:News and Views E60- E62. Boylan, K., Serr, M. and Hays, T.S. (2000) A molecular genetic analysis of the interaction between cytoplasmic dynein intermediate chain and the Glued (dynactin) complex, Mol. Biol. Cell 11:3791-3803. Martin, M.A., Iyadurai, S.J., Gindhart, J., Hays, T.S. and Saxton, W.M. (1999) Cytoplasmic dynein, the dynactin complex and kinesin are interdependent and essential for fast axonal transport. Mol. Biol. Cell 10(11):3717-3728. Robinson, J.R., Wojcik, E., Sanders, M., McGrail, M. and Hays, T.S. (1999) Cytoplasmic dynein is required for the nuclear attachment and migration of centrosomes during mitosis in Drosophila. J. Cell Biol. 146:597-608. To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed search menu should say PubMed type Hays TS in the avaliable line back to top |
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