Thomas Hays, PhD

Research Techniques:

protein biochemistry, molecular genetics (e.g., transgenic organisms), classical genetics (e.g., isolation of mutations), molecular cytology; confocal and conventional light microscopy

Research Interests:

The Hays’ lab studies the structural and regulatory mechanisms that drive intracellular transport.  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 communication an underlie a growing list of medical maladies including cancer and neurodegeneration. The Hays’ laboratory is applying genetic, molecular and biochemical approaches in Drosophila to study the molecular regulation of motor proteins and intercellular transport.
 
Mitotic mechanisms:Our mutational analysis of the Drosophila dynein motor protein revealed its essential functions in zygotic development and cell viability. We extended these analyses to characterize dynein function in mitotic cell divisions within living embryos. High speed confocal microscopy was used to monitor the progression of mitosis in wild type and mutant animals. This approach has identified multiple dynein-dependent mitotic functions. Current work is directed at understanding how dynein regulates checkpoint signaling and the progression of mitosis. Checkpoint proteins accumulate on the kinetochores of chromosomes and prevent mitotic progression from metaphase to anaphase. We recently showed that dynein actively transports checkpoint proteins off kinetochores and along the attached microtubules. The removal of kinetochore checkpoint proteins shuts off checkpoint signaling and promotes anaphase onset.

Motor phosphorylation: Protein phosphorylation is an important mechanism for controlling protein interactions and function. In collaboration with John Yates (Scripps), we are using mass spectrometry to determine the in vivo phosphorylation sites in subunits of Drosophila cytoplasmic dynein. Our first efforts are focused on the unique dynein light intermediate chain (LIC) subunit. Phosphorylation is known to regulate the progression of mitosis and we are testing the hypothesis that LIC phosphorylation regulates the coupling of dynein and checkpoint proteins at the kinetochore. We will also ask whether the state of LIC phosphorylation controls vesicle attachment and/or transport in motor neurons and dendrites. To analyze the functional signficance of identified phosphorylation sites, target residues are systematically mutated and mutant transgenes expressed in vivo.

Neuronal transport: The extended morphology of axons and dendrites makes post-mitotic neurons especially dependent on polarized transport, and ideal for studying the regulation of transport. In neurons, motor proteins transport critical signals over long distances to regulate neuronal survival and cell death, as well as to trigger the onset of neurodegenerative disease or neuronal regeneration. The perturbation of axonal transport may represent a common pathogenic mechanism underlying neurodegenerative diseases including Huntington’s disease, Parkinson’s disease, Alzheirmer’s disease and Amyotrophic Lateral Sclerosis, and Spinocerebellar Ataxias. Our recent efforts are directed at studying neuronal transport in Drosophila to ask whether disruption of transport is a convergence point in the development of neurodegenerative disease. We are pursuing the gene products and mechanisms that regulate motor proteins, and neuronal transport in Drosophila (fly) models of neurodegeneration. 

Selected Publications:

Lorenzo D.N., Li M.G., Mische S.E.., Armbrust K.R., Ranum L.P, and T.S. Hays. 2010. Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila. J. Cell Biol. 189:143-58.

Anderson MA, et al. 2009. Asunder is a critical regulator of dynein-dynactin localization during Drosophila spermatogenesis. Mol. Biol. Cell 2709-21.

Mische S, He Y, Ma L, Li M, Serr M, Hays TS. 2008. Dynein light intermediate chain: an essential subunit that contributes to spindle checkpoint inactivation. Mol. Biol. Cell 19: 4918-29.

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., 121:2643-51.

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.

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