Dartmouth College, Department of Biological Sciences, Hanover, NH 03755
Regulation of Chromosome Segregation During Meiosis
One of the most critical aspects of cell division is the accurate partitioning of genetic material into the daughter cells. During DNA replication, connections between the newly formed sister chromatids are established. “Cohesion” between sisters is required for proper orientation of chromosomes on the mitotic spindle and when cohesion is released during anaphase the sisters are able to segregate to opposite poles. Regulation of cohesion (establishment, maintenance and release) is a critical part of every cell cycle.
During meiosis, cohesion not only holds sisters together, but also plays an essential role in meiotic recombination and maintaining the association of recombinant homologues until anaphase I. The release of cohesion during meiosis is also unique—arm cohesion is dissolved during anaphase I but centromeric cohesion must be maintained until anaphase II. Therefore, normal regulation of meiotic cohesion requires additional control mechanisms that are not present during mitosis.
Defects in meiotic cohesion lead to the production of aneuploid gametes. In humans, approximately 15% of conceptions spontaneously abort because of aneuploidy and the leading known cause of mental retardation is trisomy 21. In addition, although increased maternal age has long been correlated with errors in human meiotic chromosome segregation, the underlying molecular defects that cause reduced fidelity of chromosome segregation in older oocytes are largely unknown.
The long-term goal of my lab is to define the pathway of events necessary for the proper regulation of sister-chromatid cohesion and chromosome segregation during meiosis and to understand the molecular events that cause reduced fidelity of meiotic chromosome segregation in older oocytes. We are using the model system Drosophila melanogaster to understand the mechanisms that govern meiotic cohesion and chromosome segregation. Analysis of meiosis in fruit flies allows us to capitalize upon a number of genetic techniques to identify proteins required for normal segregation and cytological methods to monitor the morphology and behavior of meiotic chromosomes. Because the process of meiosis is so highly conserved, our research provides a framework to understand the defects in meiotic chromosome segregation that lead to disease in humans.
In the last few years we have delineated a number of critical roles that cohesion plays during meiosis including chiasma maintenance and how chromatids preferentially choose a homologue (and not their sister) during recombination. We have characterized the localization and dynamics of several proteins involved in meiotic cohesion. In addition we have used fruit flies to develop a model system to study why older oocytes are more susceptible to meiotic segregation errors.