Investigating the discrete functions of the aurora kinases in meiosis I

Rutgers, The State Univ Of N.J., New Brunswick NJ

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Abstract

Project Summary Aneuploidy, the situation in which a cell has too many or too few chromosomes, is the leading genetic abnormality causing infertility, miscarriage, and failure in in vitro fertilization. Maternally derived errors in the first meiotic division are one of the primary sources of these aneuploidies. Understanding the mechanisms that regulate chromosome segregation in female gametes is critical to understanding why this unique cellular division is so error prone. The Aurora kinases are a conserved family of serine/threonine kinases critical for the regulation of accurate chromosome segregation in mitosis and meiosis. Aurora Kinase A (AURKA) and Aurora Kinase B (AURKB) are expressed in both mitotic and meiotic cells; however, Aurora Kinase C (AURKC) is only found in mammalian germ cells. The cellular functions of AURKA and AURKB in mitosis have been well defined, however, the function of the AURK's in meiosis is less understood. Due to the high sequence homology within the family studying the roles of the AURKs in meiosis has proven difficult. In this proposal I will utilize single and double knockout mouse lines in conjunction with novel genetic techniques to define the specific functions of the Aurora kinases in meiosis. In addition I will investigate the ability for AURKA to functionally compensate for AURKB and AURKC in vivo. Results from this proposal will determine how the specificity of aurora kinase function is established and the molecular mechanisms by which the family mediates accurate chromosome segregation in meiosis I. This research will help bring clarity to the field in regards to the roles of the AURKs in female meiosis and may shed light onto why this cellular division is so error prone. Hypothesis 1: AURKB maintains non-overlapping functions from AURKC in female meiosis. Aim I: AURKB is required for female meiosis to maintain the spindle assembly checkpoint and sister chromatid cohesion. Hypothesis 2: AURKA is capable of maintaining AURKB and AURKC specific functions in vivo. Aim 2: Examine the compensatory ability of AURKA to maintain canonical AURKB and AURKC functions in meiosis.