graduate student, rutgers university
Examining why female germ cells (oocytes) are highly error prone, often leading to infertility
My research aims to understand why female eggs are highly prone to errors that lead to infertility. Chromosome segregation in oocytes is a prolonged process, beginning in the developing fetus and not completing until ovulation, often decades later. Our research aims at understanding the mechanisms of chromosome segregation in female meiosis using the mouse oocyte model system. We are interested in the role of the aurora kinases in regulating chromosome segregation. Uniquely, mammalian germ cells require three aurora kinases, unlike mitotic cells which rely on two. We hypothesize that the addition of a third aurora kinase allows germ cells a selective advantage through a division of labor between the kinases. Separation of function among the family allows oocytes to respond to changing environmental situations while simultaneously providing sufficient enzymatic activity to regulate a prolonged cell division. Genetic disturbance of these kinases leads to failure to successfully complete meiosis and either subfertility or infertility. Understanding the diverse functions of these kinases is critical to understanding female fertility as multiple mutations in the aurora kinases have been identified in humans struggling with infertility.
Abstract: The aurora kinases (AURKs) comprise an evolutionarily conserved family of serine/threonine kinases involved in mitosis and meiosis. While most mitotic cells express two AURK isoforms (AURKA and AURKB), mammalian germ cells also express a third, AURKC. Although much is known about the functions of the kinases in mitosis, less is known about how the three isoforms function to coordinate meiosis. This review is aimed at describing what is known about the three isoforms in female meiosis, the similarities and differences between kinase functions, and speculates as to why mammalian germ cells require expression of three AURKs instead of two.
Pub.: 01 Apr '17, Pinned: 28 Jun '17
Abstract: Aurora B kinase (AURKB) is the catalytic subunit of the chromosomal passenger complex (CPC), an essential regulator of chromosome segregation. In mitosis, the CPC is required to regulate kinetochore microtubule (K-MT) attachments, the spindle assembly checkpoint, and cytokinesis. Germ cells express an AURKB homolog, AURKC, which can also function in the CPC. Separation of AURKB and AURKC function during meiosis in oocytes by conventional approaches has not been successful. Therefore, the meiotic function of AURKC is still not fully understood. Here, we describe an ATP-binding-pocket-AURKC mutant, that when expressed in mouse oocytes specifically perturbs AURKC-CPC and not AURKB-CPC function. Using this mutant we show for the first time that AURKC has functions that do not overlap with AURKB. These functions include regulating localized CPC activity and regulating chromosome alignment and K-MT attachments at metaphase of meiosis I (Met I). We find that AURKC-CPC is not the sole CPC complex that regulates the spindle assembly checkpoint in meiosis, and as a result most AURKC-perturbed oocytes arrest at Met I. A small subset of oocytes do proceed through cytokinesis normally, suggesting that AURKC-CPC is not the sole CPC complex during telophase I. But, the resulting eggs are aneuploid, indicating that AURKC is a critical regulator of meiotic chromosome segregation in female gametes. Taken together, these data suggest that mammalian oocytes contain AURKC to efficiently execute meiosis I and ensure high-quality eggs necessary for sexual reproduction.
Pub.: 04 Mar '14, Pinned: 28 Jun '17
Abstract: Klinefelter syndrome and Y-chromosomal microdeletion analyses were once the only two genetic tests offered to infertile men. Analyses of aurora kinase C (AURKC) and DPY19L2 are now recommended for patients presenting macrozoospermia and globozoospermia, respectively, two rare forms of teratozoospermia particularly frequent among North African men. We carried out genetic analyses on Algerian patients, to evaluate the prevalence of these syndromes in this population and to compare it with the expected frequency of Klinefelter syndrome and Y-microdeletions. We carried out a retrospective study on 599 consecutive patients consulting for couple infertility at the assisted reproduction unit of the Ibn Rochd Clinique, Constantine, Algeria. Abnormal sperm parameters were observed in 404 men. Fourteen and seven men had typical macrozoospermia and globozoospermia profiles, respectively. Molecular diagnosis was carried out for these patients, for the AURKC and DPY19L2 genes. Eleven men with macrozoospermia had a homozygous AURKC mutation (79%), corresponding to 2.7% of all patients with abnormal spermograms. All the men with globozoospermia studied (n = 5), corresponding to 1.2% of all infertile men, presented a homozygous DPY19L2 deletion. By comparison, we would expect 1.6% of the patients in this cohort to have Klinefelter syndrome and 0.23% to have Y-microdeletion. Our findings thus indicate that AURKC mutations are more frequent than Klinefelter syndrome and constitute the leading genetic cause of infertility in North African men. Furthermore, we estimate that AURKC and DPY19L2 molecular defects are 10 and 5 times more frequent, respectively, than Y-microdeletions.
Pub.: 16 Sep '14, Pinned: 28 Jun '17