Meiosis is the process by which diploid precursors replicate their DNA (to become 4n) and then undergo two successive divisions to reduce their chromosome content to haploid numbers (n) for subsequent sexual reproduction. In most species studied, meiosis is highly conserved at the molecular level and is very stringently controlled to ensure that chromosomal errors are not transmitted to subsequent generations.
Prophase I is the defining event of meiosis, since this stage is the one that is unique to this type of cell division. During prophase I, two key events happen: firstly, homologous chromosomes pair and become intimately tethered together in a process known as synapsis, and secondly, they then exchange DNA in order to further tether themselves together via DNA:DNA interactions. Thus, synapsis, which is mediated by a protein structure called the synaptonemal complex, and DNA tethering, mediated by the process of reciprocal recombination (or crossing over), both serve to keep homologous chromosomes together until the first meiotic division, at which time homologous chromosomes segregate to two distinct daughter cells.
During meiosis II, these homologous chromosomes, which each consist of a replicated pair of sister chromatids, undergo a second division which is reminiscent of a mitotic division, in which the sister chromatids separate into daughter cells. In males, this yields four haploid gametes, while in females, only one haploid gamete is produce, while the “waste” chromosomes get expelled into two polar bodies.
The Cohen and Schimenti labs have focussed extensively on mouse models that illuminate key events in mammalian meiosis. Using ENU mutagenesis approaches, the Schimenti lab have uncovered numerous key genes involved in different meiotic processes ranging from cohesion to double strand break repair and checkpoint signaling. By contrast, the Cohen lab have focussed more specifically on the role of the DNA mismatch repair pathway (and other DNA damage pathway components) in driving meiotic recombination in the mouse and human.
Figure 1. Localization of MLH1 (red) on the synaptonemal complex (SYCP3 in green) of pachytene mouse spermatoctyes. From the Cohen lab.
Copyright Paula E. Cohen, 2012
A new study from Andrew Grimson's lab, in collaboration with Paula Cohen's lab, has identified a key pathway required for maintenance of sex chromosome telomere integrity. Using conditional knockout mice for Dicer and Dgcr8, two key enzymes required for small RNA processing, Modzelewski et al (2015) show that loss of small RNAs during prophase I leads to telomere fusion events specifically involving the X and Y chromosomes. For further information, see the May edition of Journal of Cell Science
A recent publication by Dabaja et al (2015) has identified key cell:cell interactions that are necessary to establish normal profiles of one key microRNA, miR202-5p, in Sertoli cells. This is the first example of a germ cell regulatory interaction that is necessary for miR expression in neighboring somatic cells of the testis
The lab of Center member John Schimenti recently identified the DNA damage checkpoint pathway responsible for culling oocytes that fail to repair double stranded breaks (DSBs) that occur during meiosis or which arise in a female's oocyte pool (Bolcun-Filas et al, Science 343:533-536, 2014). Using combinations of mutants involved in recombination and DNA damage responses, they found that this pathway involves signaling of checkpoint kinase 2 (CHK2) to both p53 and p63. Disruption of this checkpoint pathway restored fertility to females that normally would be deficient of all oocytes due to defects in meiotic recombination or exposure to radiation. This discovery opens the way to using available CHK2 inhibitors to protect the oocytes of women undergoing cancer therapy that would normally cause infertility.