Yixian Zheng

Microtubule Nucleation and Organization in Response to Cell Cycle and Developmental Signals

How a cell organizes its interior and how it divides are central questions in cell and developmental biology. Research in the Zheng lab focuses on understanding how different microtubule arrays are nucleated and are organized in response to cell cycle and developmental signals. Microtubules are tiny filaments found in all eukaryotes. They are essential for intracellular organization and mitosis.

The major microtubule nucleation site inside an animal cell is the centrosome. One research avenue in the Zheng lab is to understand the structure and function of the centrosome using Xenopus and Drosophila as model systems. The centrosome consists of a pair of centrioles and an electron-dense pericentriolar material (PCM), which harbors the activity for microtubule nucleation and organization. The scientists in Zheng's lab discovered a g-tubulin-containing ring complex (gTuRC) in the two organisms and found that it can nucleate microtubules in vitro. Additionally they found that gTuRC is essential for centrosomes to nucleate microtubules. Zheng's current hypothesis is that the gTuRC is the major microtubule nucleator at the PCM. gTuRC consists of approximately five, presently uncharacterized, proteins in addition to g-tubulin. The team is using a combination of molecular genetic, biochemical, and genetic approaches to understand this ring complex. The researchers are particularly interested in addressing how the gTuRC is involved in regulating microtubule-nucleating activity of the centrosome, how it is recruited and assembled at the PCM, and whether (and how) it is involved in centrosome duplication.

Another research direction in the lab is to understand the signals that regulate spindle assembly during mitosis. In animal cells, the transition from interphase to mitosis is accompanied by dramatic changes in cellular architecture such as nuclear envelope breakdown, chromosome condensation, and spindle formation. 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 found that nuclear signals released into the cytoplasm upon nuclear envelope breakdown exert many different effects on microtubule arrays. Recently, the Zheng group discovered that the small nuclear GTPase, Ran, can stimulate microtubule aster and spindle formation in the absence of both centrosomes and chromosomes. These findings suggest that Ran is the nuclear signal that regulates microtubule assembly in mitosis.

Future projects in the lab will involve dissecting the mechanism of the Ran signaling pathway in mitosis. The Zheng lab has shown that RanGTP can stimulate not only microtubule polymerization but also microtubule organization in mitosis. They are now developing assays to help identify the downstream targets of RanGTP.