[ Research Interests ] [ Representative Publications ]

Yixian Zheng, Ph.D. Adjunct Associate Professor Department of Biology Assistant Investigator HHMI Staff Member Carnegie Institution of Washington B.S. (Biology) Sichuan University, PR China Ph.D. (Molecular Genetics) Ohio State University

Carnegie Institution of Washington 3520 San Martin Drive Baltimore, MD 21218 U.S.A. Office Telephone: Lab Telephone: Department Fax: Email: 410-246-3032 410-246-3030 410-243-6311 zheng@ciwemb.edu Carnegie Institution of Washington

Research Interests Microtubule Nucleation and Organization During the Cell Cycle How a cell organizes its interior and divides are central questions in cell and developmental biology. Research in my lab focuses on understanding how the cell nucleates and organizes microtubules to achieve intracellular organization and cell division. The major microtubule nucleation site inside an animal cell is the centrosome. One research avenue in my lab is tounderstand the structure and function of the centrosome using Xenopus , Drosophila , and mammalian tissue culture cells.The centrosome consists of a pair of centrioles and an electron-dense pericentriolar material (PCM) which harbors the activity for microtubule nucleation and organization. We discovered a g Tubulin containing Ring Complex (gTuRC) and showed that it can nucleate microtubules in vitro. Furthermore, we found, that gTuRC is essential for centrosomes to nucleate microtubules. Our current hypothesis is that the gTuRC is the majormicrotubule nucleator at the PCM. gTuRC consists of approximately 6 presently uncharacterized proteins in addition to g tubulin. We are using a combination of molecular genetic, biochemical and genetic approaches to understand this ring complex. We are particularly interested in addressing how the gTuRC is involved in regulating microtubule nucleating activity of the centrosome, how it is recruited to and assembled at the PCM and whether and how it is involved in centrosome duplication. In animal cells, the transition from interphase to mitosis is accompanied by dramatic changes in cellular architecture such as nuclear envelope break down, chromosome condensation and spindle formation. Another direction in my lab is to understand the signals that regulate spindle assembly during mitosis. The reorganization of the interphase microtubule array into a highly dynamic mitotic spindle requires more than the presence of centrosomes and the conversion of cytosol into a mitotic state. Several studies have shown that nuclear signals released into the cytoplasm upon nuclear envelope breakdown exert many different effects on microtubule arrays. Recently, we discovered that the  nuclear GTPase, Ran, can stimulate microtubule aster and spindle formation in the absence of both centrosomes and chromosomes. Our findings suggest that Ran is the nuclear signal that regulates microtubule assembly in mitosis. Recently we found that a carboxyl-terminal region of the nuclear mitotic apparatus protein (NuMA), a nuclear protein required for organizing mitotic spindle poles, mimics Ran's ability to induce microtubule asters. This NuMA fragment also specifically interacted with the nuclear transport factor, importin-b, a receptor for protein import into the nucleus.Importin-b is an inhibitor of microbutule assembly in Xenopus egg extracts, and Ran regulates the interaction between importin-B and NuMA.Importin-b therefore links NuMa to regulation by Ran.This suggests that similar mechanisms regulate nuclear import during interphase and spindle assembly during mitosis. Considering the complexity of spindle assembly, other mitotic microtubule regulators are likely to be regulated by Ran through importin-b. Indeed, several characterized microtubule regulators were found to be nuclear in interphase, suggesting an interaction with the nuclear import pathway.Based on our findings, we hypothesize that Ran may regulate the activity of these proteins in mitosis via importin-b. The next challenge is to understand the mechanism of importin-b-mediated regulation of spindle assembly. Representative Publications Kawaguchi S and Zheng Y. (2004) Characterization of a Drosophila Centrosome Protein CP309 That Shares Homology with Kendrin and CG-NAP. Molecular Biology of the Cell 15, 37-45. Li HY and Zheng Y. (2004) Mitotic phosphorylation of RCC1 is essential for RanGTP gradient production and spindle assembly in mammalian cells. Genes and Development, 18, 512-527. Gunawardane R, Martin OC, and Zheng Y. (2003) Characterization of a new gTuRC subunit with WD repeats. Molecular Biology of the Cell 14, 1017-1026. Tsai MY, Wiese C, Cao K, Martin OC, Donovan P, Ruderman J, Prigent C, and Zheng Y. (2003) A Ran-signaling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nature Cell Biology 5, 242-248. Li HY, Wirtz D, and Zheng Y. (2003) A mechanism of coupling RCC1 mobility to RanGTP production on the chromatin in vivo. Journal of Cell Biology 160, 635-644. Cao K, Nakajima R, Meyer HH, and Zheng Y. (2003) The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis. Cell 115, 355-367. Wilde A, Lizarraga S, Zhang L, Wiese C, Gliksman N, Walczak C, and Zheng Y. (2001). Ran stimulates spindle assembly by changing microtubule dynamics and the balance of motor activities. Nature Cell Biology 3, 221-227. Wiese C, Wilde A, Adam S, Moore M, Merdes A, and Zheng Y. (2001). Role of Importin-b in Coupling Ran to Downstream Targets in Microtubule Assembly. Science 290, 653-656. Wiese C and Zheng Y. (2000). A New Function for the g-tubulin Ring Complex as a Microtubule Minus-end Cap. Nature Cell Biology 2, 358-364. Zhang L, Keating T, Wilde, A, Borisy G, and Zheng Y. (2000). The Role of Xgrip210 in g-Tubulin Ring Complex Assembly and Centrosome Recruitment. Journal of Cell Biology 151, 1525-1535. Gunawardane R, Martin O, Cao K, Zhang L, Dej K, Iwamatsu A, and Zheng Y. (2000). Characterization and Reconstitution of Drosophila g-Tubulin Ring Complex Subunits. Journal of Cell Biology 151, 1513-1523. Oegema K, Wiese C, Martin OC, Milligan RA, Iwamatsu A, Mitchison T, and Zheng Y. (1999). Characterization of Two Related Drosophila g-tubulin Complexes that Differ in Their Ability to Nucleate Microtubules. Journal of Cell Biology 144, 721-733. Wilde A and Zheng Y. (1999). Stimulation of Microtubule Aster Formation and Spindle Assembly in Xenopus Egg Extracts by the Small GTPase Ran. Science 284, 1359-1362. Martin O, Gunawardane R., Iwamatsu A, and Zheng Y. (1998). Xgrip109: A g-tubulin associated protein with an essential role in gTuRC assembly and centrosome function. Journal of Cell Biology 141, 675-687. Moritz M, Zheng Y, Alberts B, and Oegema K. (1998). Recruitment of the g-tubulin ring complex to Drosophila salt-stripped centrosome scaffolds. Journal of Cell Biology 142, 775-786. Zheng Y, Wong ML, Alberts B, and Mitchison TJ. (1995). A g-tubulin ring complex from the unfertilized egg of Xenopus laevis can nucleate microtubule assembly in vitro. Nature 378, 578-583. Zheng Y, Jung MK, and Oakley BR. (1991). g-tubulin is present in Drosophila melanogaster and Homo sapiens and is associated with the centrosome. Cell 65, 817-823.

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