Cell cycle kinases and meiosis
Meiosis, a defining event of gametogenesis, is a specialized cell division involving one round of chromosome replication followed by two rounds of chromosome segregation (meiosis I and II),
resulting in the formation of up to four haploid gametes. During the reductional meiosis I division, homologous chromosomes segregate and the sister chromatids remain associated until their segregation in the equational division of meiosis II.
Polo-like kinases and Aurora kinases
Several families of protein kinases orchestrate the complex events that drive the meiotic cell cycle, and deregulation of their activity can cause errors that may result in aneuploidy, developmental defects and infertility. Our lab is using mutant mouse models and phopho-proteome analyses to determine the novel regulatory roles of Polo-like kinases and Aurora kinases during meiosis. We are focusing on the following processes:
Homologous chromosome recombination and synapsis
For homologous chromosomes to segregate correctly during meiosis I, they must first become physically associated with one another. This association is achieved via crossover recombination between homologous chromosomes and the formation of a proteinaceous complex known as the synaptonemal complex (SC) that bridges the homologous chromosomes together.
The physical association between homologous chromosomes occurs during prophase I of meiosis, which is partitioned into four sub-stages - Leptotene, Zygotene, Pachytene and Diplotene.
Our lab is determining the regulatory roles for Polo-like kinases during these stages of meiosis.
Lynn et al., Chrom. Res., 2007
Synaptonemal complex disassembly
In most organisms, including mammals, homologous chromosome synapsis and recombination is facilitated by a zipper-like tripartite protein complex known as the synaptonemal complex (SC). The SC is comprised of two lateral elements that form the core of each homolog and a series of transverse filaments known as the central element, which bridges the two lateral elements.
The crucial event of exit from meiotic prophase and initiation of the meiosis I division phase is desynapsis, or disassembly of the tripartite SC. The disassembly of the SC initiates during the
diplotene stage, when components of the central element dissociate from the chromatin, remaining only at chromosome ends and sites of crossovers. Errors during SC disassembly can result in chromosome missegregation and infertility.
Our ongoing studies implicate roles for Polo-like kinases and Aurora kinases in regulating
Sun and Handel, Chromosoma 2008
Crosstalk between the nucleus and the centrosome
We are elucidating how chromosome and centrosome dynamics are coordinately regulated during meiotic prophase I to ensure fertility and healthy embryonic development. We are combining the use of mutant mouse models with phosphoproteomic and molecular approaches to further test our hypothesis that Polo-like kinases mediate cross-talk between nuclear and centrosomal processes throughout meiotic prophase I.