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 consisting of microtubules, microtubule-associated proteins (MAPs), and motors. The spindle also associates with many poorly defined proteins and membranes. Historically these spindle-associated materials are called the spindle matrix. The importance of the spindle matrix and the value of studying it have remained a subject of debate.

We have uncovered protein complexes called γ-tubulin ring complex (γTuRC) and γ-tubulin small complex (γTuSC) that mediate microtubule nucleation and organization in mitotic 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, we and others have uncovered an important signaling pathway mediated by the nuclear small GTPase Ran that regulates multiple aspects of cell division. We show that RanGTPase also regulates the assembly of the spindle matrix containing lamin-B. Based on our studies, we propose that RanGTP and the spindle matrix promote both spindle assembly and orientation. Consistent with this, we show that the spindle matrix component lamin-B regulates spindle orientation in neural stem cells in the developing mouse brain. Lamin-B may do so in part by regulating centrosome positioning.

The complexity of the spindle matrix has made the study of its structure and function relationship very difficult, which contributes to the debate of its function and even existence. By studying another spindle matrix component BuGZ, which we discovered through proteomic analyses of the Xenopus spindle matrix, we show that protein phase separation/transition represents a biophysical property of the spindle matrix. The phase separation of BuGZ along spindle microtubules promotes spindle matrix assembly, which in turn facilitates spindle microtubule assembly by concentrating tubulin. This finding opens the door to further characterize the structure and function of the spindle matrix in cell division.

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 (such as ChIP-seq, RNA-seq, single cell RNA-seq, and Hi-C), cell biology, and biochemistry to study how genomes obtain their organization in stem cells (including ES cells) and differentiated cells isolated from tissues. 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 studies demonstrate that lamin-B (the major structural component of the nuclear lamina) is not required for early lineage specification during development, but it is essential for proper organogenesis. Aging-associated lamin-B reduction in Drosophila fat bodies (equivalent to human fat and liver) leads to system inflammation and gut hyperplasia. These and other published and ongoing studies in the lab are allowing us to dissect the role of genome organization in the context of development, tissue function, and aging.

Many cnidaria species, including Hydra, upside-down jellyfish, and hard and soft corals harbor algae for photosynthesis. The algae live inside coral cells in a specialized membrane compartment called symbiosome, which shares the photosynthetically fixed carbon with coral host cells, while host cells provide inorganic carbon for photosynthesis. The molecular pathways in cnidaria cells that orchestrate algal recognition, uptake, nutrient sharing, and maintenance remain poorly understood. We have built facilities to grow various cnidaria species and have begun to create model organisms to understand cnidaria endosymbiosis.