Systems biology of cell division and nuclear organisation
Figure 1: Meiotic spindle of a mouse oocyte. Chromosomes (blue) are biooriented by the meiotic spindle microtubules (green) at their kinetochores (red).
The Ellenberg group studies how cells divide and organise in mitosis and meiosis, where errors can lead to problems such as cancer and infertility.
Previous and current research
The genome of eukaryotic cells is compartmentalised inside the nucleus, delimited by the nuclear envelope (NE) whose double membrane is continuous with the endoplasmic reticulum and perforated by nuclear pore complexes (NPCs). In M-phase, most metazoan cells reversibly disassemble the nucleus. Chromosomes are condensed, attached to cytoplasmic spindle microtubules, faithfully segregated and decondensed, and the nucleus rapidly reassembles. Errors in this beautiful cycle of cell division can lead to severe consequences, such as cancer in somatic cells and infertility in gametes.
The overall aim of our research is therefore to systematically elucidate the mechanisms underlying cell division and nuclear organisation in mitosis and meiosis. To achieve this, we are developing advanced fluorescence microscopy-based methods to systematically identify the required proteins and study their function in living cells. Quantitative imaging is coupled with computerised image processing and simulations to extract biophysical parameters and build mechanistic models. As biological systems, we are using somatic human cells for mitosis and cancer, and mouse oocytes and early embryos for meiosis and infertility.
In the recent past we showed that mitotic nuclear breakdown and reformation is initiated by the ordered dis- and reassembly of NPCs, which interestingly use a different pathway to assemble during interphase. Furthermore, we demonstrated that meiotic spindle assembly and asymmetric positioning rely on novel mechanisms and that meiotic chromosome biorientation is highly error prone (figure 1). We have also identified hundreds of new cell division genes by screening the entire human genome using time-lapse microscopy (figure 2).
Figure 2: Mitotic spindle composed of thousands of microscopy images of human cells in which individual genes were silenced. Chromosomes (red) are made of images from genes that affect their segregation, while the mitotic spindle (green) is composed of images from genes affecting its assembly.
Future projects and goals
The objective of our future work is to gain comprehensive mechanistic insight into the division of human mitotic cells, to establish methods for systems analysis of the meiotic and first mitotic divisions of mammalian oocytes and embryos, and to provide a biophysical basis to understand nuclear organisation.
For mitosis, we are aiming to achieve a systems-level understanding of all proteins identified in our phenotypic profiling of the human genome. To this end we are continuously automating advanced fluorescence imaging and single molecule techniques to study protein function in live cells in high throughput.
For oocyte meiosis and early embryonic mitosis, we are pursuing the molecular mechanism of homologous chromosome segregation and are developing new gene silencing methods and light sheet-based imaging systems to establish a physiological model for infertility accessible for systems biology.
For nuclear organisation, we are currently focusing on the structure and assembly of the nuclear pore, the targeting and function of inner nuclear membrane proteins, and chromosome architecture and dynamics.