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Investigating how anaphase chromosomal motion is generated during mitosis and meiosis

Periodic Reporting for period 1 - ChromoDrive (Investigating how anaphase chromosomal motion is generated during mitosis and meiosis)

Reporting period: 2017-07-01 to 2019-06-30

Cell division is a process essential for life. There are two types of cell division in mammalian cells: meiosis and mitosis. Meiosis is a type of cell division specific to germ cells, allowing the formation of fertilisation-competent sperm and eggs. Mitosis allows a single-celled fertilised egg to develop into a mature organism, and also allows hair, skin, blood cells, and internal organs to be renewed. During each cell division, the cell must divide two copies of the genome equally between two daughter cells. Errors that occur during this process in the oocyte can lead to spontaneous abortion and birth defects, whilst errors occurring in somatic cells lead to genetic instability, and are a hallmark of cancer. It is therefore essential to understand how this fundamental process occurs.
The phase of cell division during which the chromosomes are physically separated is called anaphase. Although anaphase has fascinated generations of scientists for more than a century, the mechanisms that underlie the poleward movement of the chromosomes in mammals are still unclear. Several studies have suggested candidate proteins that may power their movement, however there were no conclusive results due to the technically challenging nature of this research. The main reason for this challenge is that one must efficiently inactivate the candidate protein(s) only at the onset of anaphase so as to avoid disrupting the previous phases of cell division, which could confound the results.
Technologies to rapidly inactivate proteins of interest have recently become available. Here, we proposed to use these techniques to systematically dissect the mechanism(s) underlying poleward chromosome movement during anaphase in both mammalian germ cells (oocytes, meiosis) and non-transformed mammalian somatic cells (mitosis) in order to understand how chromosomes are separated during anaphase.
We attempted to screen through known proteins that might account for anaphase chromosomal motion in mouse oocytes using a newly developed technique. However, this proved technically difficult, and we changed our experimental strategy. Instead of mouse oocytes, we used a cell type that is less sensitive to manipulation, and which has a very low number of chromosomes. This is advantageous, as it allows us to visualise and track the movement of individual chromosomes. Using this cell type, we found that, contrary to what was typically thought to happen in anaphase, chromosomes do not move continuously towards the spindle poles; rather, they undergo to-and-fro oscillations.
We characterised these movements by depleting candidate proteins and using drugs to acutely inhibit targets to investigate how these movements are controlled in the cell. We found several proteins which govern these oscillations, as well as the overall movement of chromosomes towards the poles, and are continuing to investigate how these proteins generate the force to move chromosomes towards the poles.
As our average population gets older, cancer rates are increasing. Women are also choosing to bear children at more advances ages, which carries increased risks of birth defects and miscarriage. Cancer, birth defects, and miscarriages are all linked to the incorrect separation of chromosomes during cell division. It is therefore crucial to understand how chromosomes are separated during anaphase in order to understand why errors occur during this process, and how to avoid them.
Our results have helped to understand what happens during anaphase and how chromosomes move towards the spindle poles. We have found several proteins which control this process, which have the potential to be used as therapeutic targets in fertility treatment and diseases such as cancer. For example, we may be able to target these proteins to cause a catastrophic anaphase, thereby pushing cancer cells to die by apoptosis. Conversely, we may be able to understand if these proteins are affected in the eggs of older women, and find treatments to improve the fidelity of chromosome segregation.
A mouse oocyte in metaphase II (green: meiotic spindle, magenta: chromosomes)