My lab has a long-standing interest in cell division. In recent years, the findings we have made have broadened our research scope to include the study of stem cells, genome organization, and lineage specification using animal models. We have three research areas. 1. The mechanism of cell division. 2. The mechanism of genome organization in development, homeostasis, and aging. 3. The influence of cell morphogenesis on cell fate decisions.We use a wide range of tools and systems, including genetics in model organisms, cell culture, biochemistry, proteomics, genomics in our research. I will briefly summarize each of the research areas with selected publication links. For a full list of papers please refer to the complete Publication list. You can also learn how I became a scientist by visiting the external YouTube links: How I Became a Scientist (In English) and/or How I Became a Scientist (In Chinese).
The way a progenitor cell partitions itself during cell division has a profound influence on the behavior and fate of its daughter cells. Understanding this partitioning requires us to study both the mechanism of equal chromosome segregation and the means a dividing cell segregates critical cell fate determinants into daughter cells. The mitotic spindle apparatus is one of the most complex cellular machines essential for cell division. It nucleates and organizes three major types of microtubules (MTs): kinetochore MTs that capture and segregate chromosomes, astral MTs that interact with the cell cortex to position the spindle, and the pole-to-pole MTs that help to maintain the spindle morphology.
We have uncovered protein complexes called γ-tubulin ring complex (TuRC) and γ-tubulin small complex (γTuSC) that mediate microtubule nucleation and organization in both mitosis and interphase cells. Through the study of microtubule nucleation, we became fascinated by the more complex and dynamic behaviors of microtubules during mitotic spindle assembly. By using the powerful Xenopus egg extract system, we have uncovered an important signaling pathway mediated by the nuclear small GTPase Ran that regulates multiple aspects of cell division. These include mitotic progression, microtubule organization, and the assembly of a lamin-B containing membranous spindle matrix. Based on these studies, we have proposed that RanGTP and the spindle matrix are critical in regulating spindle orientation. Consistent with this idea, we have shown recently that lamin-B regulates spindle orientation in neural stem cells in the developing mouse brain (see below).
Our interest in this area is to further dissect the components and functions of the spindle matrix in cell division both in vitro using cell free spindle assembly assays and in vivo using neural stem cells or other progenitor cells.
1. Zheng Y, Jung MK, & Oakley BR (1991). γ-tubulin is present in Drosophila melanogasterand Homo sapiensand is associated with the centrosome. Cell 65:817-823
2. Zheng Y, Wong ML, Alberts B, & Mitchison TJ (1995). A γ-tubulin ring complex from the unfertilized egg of Xenopus laevis can nucleate microtubule assembly in vitro. Nature 378:578-583.
3. Oegema K, Wiese C, Martin OC, Milligan RA, Iwamatsu A, Mitchison T, & Zheng Y (1999). Characterization of Two Related Drosophilaγ-tubulin Complexes that Differ in Their Ability to Nucleate Microtubules. Journal of Cell Biology 144:721-733
4. Wilde A & Zheng Y (1999). Stimulation of Microtubule Aster Formation and Spindle Assembly in XenopusEgg Extracts by the Small GTPase Ran. Science 284:1359-1362.
5. Wiese C & Zheng Y (2000). A New Function for the γ-tubulin Ring Complex as a Microtubule Minus-end Cap. Nature Cell Biology 2:358-364.
6. Wilde A, Lizarraga S, Zhang L, Wiese C, Gliksman N,Walczak C, & Zheng Y (2001). Ran stimulates spindle assembly by changing microtubule dynamics and the balance of motor activities. Nature Cell Biology 3:221-227.
7. Wiese C, Wilde A, Adam S, Moore M, Merdes A, & Zheng Y (2001). Role of Importin-bin Coupling Ran to Downstream Targets in Microtubule Assembly. Science 291:653-656.
8. Tsai MY, Wiese C, Cao K, Martin OC, Donovan P, Ruderman J, Prigent C, & Zheng Y (2003). A Ran-signaling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nature Cell Biology 5:242-248
9. Cao K, Nakajima R, Meyer HH, & Zheng Y (2003). The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis. Cell 115:355-367.
10. Li HY & ZhengY (2004). Mitotic phosphorylation of RCC1 is essential for RanGTP gradient production and spindle assembly in mammalian cells. Genes and Development 18:512-527
11. Zheng Y(2004). G Protein Control of Microtubule Assembly. Annual Review of Cell and Developmental Biology 20:867-894
12. Tsai M-Y &Zheng Y (2005). Aurora A Kinase-Coated Beads Function as Microtubule-Organizing Centers and Enhance RanGTP-Induced Spindle Assembly. Current Biology 15:2156-2163.
13. Vong QP, Cao K, Li HY, Iglesias PA, & Zheng Y (2005). Chromosome Alignment and Segregation Regulated by Ubiquitination of Survivin. Science 310:1499-1504.
14. Tsai M-Y, Wang S, Heidinger JM, Shumaker D, Adam SA, Goldman RD, & Zheng Y (2006). A Mitotic Lamin B Matrix Induced by RanGTP Required for Spindle Assembly. Science 311:1887-1893.
15. Wiese C & Zheng Y (2006). Microtubule nucleation: γ-tubulin and beyond. Journal of Cell Science 119:4143-4153
16. Li M, Tsai MY, Lu B, Chen R, Yates III JR, Zhu X, & Zheng Y (2009). A Requirement of Nudel and Dynein for Spindle Matrix Assembly during Spindle Morphogenesis. Nature Cell Biology 11:247-256
17. Liu Z & Zheng Y (2009). A Requirement for Epsin in Mitotic Membrane and Spindle Organization. Journal of Cell Biology186:473-480
18. Bembenek JN, White JG, & Zheng Y (2010). A Role for Separase in the Regulation of RAB-11-positive Vesicles at the Cleavage Furrow and Midbody. Current Biology 20:259-264.
19. Zheng Y (2010). Mitotic spindle matrix may hold the answer to orchestrating cell division. Nature Reviews Molecular Cell Biology 11:529-535
20. Goodman B, Channels W, Qiu M, Iglesias P, Yang G, & Zheng Y (2010). Lamin-B3 counteracts the kinesin Eg5 to restrain spindle pole separation during spindle assembly. J Biol Chem 285:35238-44
21. Poirier CC, Zheng Y, & Iglesias PA (2010). Mitotic Membrane Helps to Focus and Stabilize the Mitotic Spindle. Biophys J 99:3182-3190
22. Wang S & Zheng Y (2011). Identification of a novel dynein-binding domain in Nudel essential for spindle pole organization in Xenopus egg extracts. J Biol Chem 286:587-93
Genome Organization in Development, Tissue Homeostasis, and Aging
The nuclear lamina and chromatin-bound proteins are known to regulate genome organization in interphase cells, yet how cells in different lineages acquire and maintain their unique genome architecture has remained poorly understood. We use various tools in genetics, genomics (ChIP-seq and RNA-seq), cell biology, and biochemistry to study how genomes obtain their organization in stem cells (including ES cells) and during development. We also analyze whether such organization plays a role in lineage specification or terminal differentiation, how such organization is maintained in adulthood, and whether genome dis-organization leads to age-associated diseases. For example, our recent study has demonstrated that lamin-B (the major structural component of the nuclear lamina) is not required for lineage specification during development, but it is essential for proper organogenesis. These and other ongoing studies in the lab are allowing us to dissect the role of genome organization in the context of development, tissue function, and aging.
1. Kim Y, Sharov AA, McDole K, Cheng M, Hao H, Fan C-M, Gaiano N, Ko MSH, & Zheng Y (2011). Mouse ES cells do not need any lamins but proper organogenesis requires lamin-Bs. Science 334:1706-1710.
2. Jia J, Zheng X, Hu G, Cui K, Zhang J, Zhang A, Jiang H, Lu B, Yates J III, Liu C, Zhao K, and Zheng Y. (2012). Regulation of pluripotency and epigenetic-threshold modulation and mRNA pruning. Cell 151:576-598.
3. Kim Y, McDole, K and Zheng Y. (2012). The function of lamins in the context of tissue building and maintenance. Nucleus 3:256-262.
The Influence of Cell Morphogenesis on Cell Fate Decisions
We use the pre-implantation mouse embryos to study how the morphology and physical property of a cell influence its transcriptional network. The development of the pre-implantation embryo affords a unique opportunity for this study because the first lineage specification occurs in a small number of initially similar cells independent of signal induction from other tissues. By applying two-photon live-imaging and computational modeling and tracking, we have uncovered unique cellular behaviors that are coupled with lineage specification during pre-implantation development. These observations have allowed us to use two-photon microscopy to further analyze how various physical and chemical perturbations of cell morphology influence the expression of lineage specification genes.
1. Vong QV, Liu Z, Yoo JG, Chen R, Xie W, Sharov AA, Fan CM, Liu C, Ko MSH, & Zheng Y (2010). A Role for Borg5 during Trophectoderm Differentiation. Stem Cells 28:1030-1038
2. McDole K, Xiong Y, Iglesias PA, Zheng Y (2011). Lineage mapping the pre-implantation mouse embryo by two-photon microscopy, new insights into the segregation of cell fates. Dev Biol. 355:239-49.
3. McDole K and Zheng Y (2012). Generation and live imaging of an endogenous Cdx2 reporter mouse line. Genesis 50:775-782.