Chromosome segregation during meiosis I (MI) is unique because homologous chromosome pairs segregate. In humans, mistakes in MI occur are strikingly high in female gametes (oocytes), resulting in infertility, miscarriage, or birth defects. The molecular mechanisms that control MI are poorly understood. The goal of this proposal is focused on dissecting the mechanisms that the Aurora B and Aurora C protein kinases use to control MI to explain this phenomenon. The Aurora protein kinase family is an essential regulator of chromosome segregation in mitosis, and Aurora activity is required for completing a normal MI segregation. Aurora C kinase (AURKC) expression is highly up- regulated in gametes. Yet, because AURKC shares high sequence homology with Aurora B kinase (AURKB) standard approaches to understand their MI-specific functions are not sufficient. We have begun to unravel the mystery of why oocytes contain 2 kinases that are similar to one another, and have identified AURKC functions during MI in mouse oocytes that are distinct from AURKB. These functions include ensuring normal chromosome alignment at the metaphase I plate and chromosome segregation to maintain proper chromosome numbers through controlling incorrect microtubule attachments to chromosomes. In this proposal, we aim to fully determine the MI functions of both AURKB and AURKC. We have generated mice that lack Aurkb and Aurkc in their oocytes to conduct more thorough analyses of AURK function using a chemical genetics strategy. This strategy will be used in Aim 1 to investigate the molecular mechanisms of AURKB and AURKC in microtubule dynamics and cytokinesis during MI.
This aim will test the hypothesis that some functions are distinct, whereas other functions are overlapping. We have demonstrated that AURKC has a unique localization along chromosome arms at the interchromatid axes during metaphase I that is not found in mitotic metaphase.
In Aim 2 we develop strategies to perturb the localized activity of AURKC at the axes to test the hypothesis this localized AURKC activity controls meiotic chromosome condensation during MI. Information gained from our studies will help us fully understand how these kinases operate during MI while highlighting distinct differences between how mitosis and MI are controlled. Importantly, these data will shed light on how MI chromosome segregation is controlled in oocytes and why it commonly goes awry in women leading to chromosome segregation errors.

Public Health Relevance

Meiosis is the process that generates eggs and sperm necessary for sexual reproduction. For reasons not completely understood, meiosis in females is highly error prone, leading to infertility, miscarriage, and birth defects. The long-term goal o this grant is to understand how meiosis occurs in eggs to shed light on why this process frequently goes awry in females.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM112801-02
Application #
9064811
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Melillo, Amanda A
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rutgers University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
001912864
City
Piscataway
State
NJ
Country
United States
Zip Code
Nguyen, Alexandra L; Drutovic, David; Vazquez, Berta N et al. (2018) Genetic Interactions between the Aurora Kinases Reveal New Requirements for AURKB and AURKC during Oocyte Meiosis. Curr Biol 28:3458-3468.e5
Nguyen, Alexandra L; Schindler, Karen (2017) Specialize and Divide (Twice): Functions of Three Aurora Kinase Homologs in Mammalian Oocyte Meiotic Maturation. Trends Genet 33:349-363
Radford, Sarah J; Nguyen, Alexandra L; Schindler, Karen et al. (2017) The chromosomal basis of meiotic acentrosomal spindle assembly and function in oocytes. Chromosoma 126:351-364
Quartuccio, Suzanne M; Dipali, Shweta S; Schindler, Karen (2017) Haspin inhibition reveals functional differences of interchromatid axis-localized AURKB and AURKC. Mol Biol Cell 28:2233-2240
Balboula, Ahmed Z; Blengini, Cecilia S; Gentilello, Amanda S et al. (2017) Maternal RNA regulates Aurora C kinase during mouse oocyte maturation in a translation-independent fashion. Biol Reprod 96:1197-1209
Balboula, Ahmed Z; Nguyen, Alexandra L; Gentilello, Amanda S et al. (2016) Haspin kinase regulates microtubule-organizing center clustering and stability through Aurora kinase C in mouse oocytes. J Cell Sci 129:3648-3660
Balboula, Ahmed Z; Stein, Paula; Schultz, Richard M et al. (2015) RBBP4 regulates histone deacetylation and bipolar spindle assembly during oocyte maturation in the mouse. Biol Reprod 92:105
Quartuccio, Suzanne M; Schindler, Karen (2015) Functions of Aurora kinase C in meiosis and cancer. Front Cell Dev Biol 3:50