Work in the Schindler laboratory is focused at understanding how meiosis in female gametes is regulated at the level of signal transduction networks that involve protein kinases and phosphatases. These signaling molecules transfer phosphate to and from protein substrates in response to a extracellular cues to illicit appropriate intracellular responses. Currently, the laboratory is determining the meiotic functions of the Aurora family of kinases.
If a mitotically dividing cell makes a chromosome segregation mistake, the cell may transform into a cancer cell. However, when a germ cell, sperm or egg, makes a chromosome segregation mistake this event can negatively impact an organism’s fertility or result in a developmental disorder like Down Syndrome. The Aurora kinases (AURKs) are highly conserved throughout evolution, and are well known for their roles in maintaining proper chromosome numbers during the mitotic cell cycle. Mammals contain 3 AURK isoforms: AURKA, AURKB and AURKC. AURKA and AURKB are expressed in nearly all cell types. AURKC is most similar in sequence to AURKB but its expression is largely limited to sperm and egg. Oocytes contain both AURKB and AURKC, but we still know little about the meiotic functions of these critical chromosome segregation regulators.
Our laboratory uses a combination of mouse genetics and cell biology to answer questions pertinent to improving women’s reproductive helath and furthering our basic understanding of how meiosis is regulated at the molecular level. Projects in the laboratory are currently aimed at the following:
1. AURKB is a critical regulator of maintaining ploidy in mitosis, but if AURKC is ectopically expressed it can compensate for loss of AURKB. Furthermore, AURKB compensates for loss of AURKC during meiosis in oocytes from AURKC knockout mice. Because of these compensatory mechanisms, the function(s) of AURKB/C during MI is still unknown. We are generating a mouse strain that lacks both AURKB/C in oocytes and are using chemical genetics to circumvent this functional redundancy with the ultimate goal to determine the function(s) of each kinase during MI.
2. AURKC localizes to centromeres and chromosome arms during metaphase I in oocytes. In the absence of AURKC, AURKB adopts this localization pattern. In mitotic metaphase, however, re-localization of AURKB from centromeres to chromosomes causes aneuploidy. Therefore, understanding the requirement for AURK activity at chromosome arms will be important for understanding how meiosis I is regulated differently than mitosis. To dissect this regulatory mechanism, we are perturbing several pathways that are required for AURKB localization during mitosis in oocytes and assessing changes in AURKB/C localization and ploidy of the resulting eggs.
3. Small nucleotide polymorphisms (SNPs) in AURKC are associated with aneuploid, large-headed sperm arrested at meiosis I in infertile men from North Africa and Europe. Using human oocytes to determine if altered AURKC function causes subfertility is impractical because of limitations in obtaining large numbers of oocytes. We are developing the AURKC knockout mouse oocyte system as a model to determine if the known SNPs alter AURKC function during meiosis.