Accurate meiotic segregation of physically and genetically intact sex chromosomes is essential for male reproduction and species survival; chromosome segregation is set up in meiotic prophase. Mutations impairing prophase chromosome dynamics lead to sterility and arrested meiosis with failure to repair DNA damage. In the spermatocyte nucleus, sex chromosomes lie in a nuclear territory distinct from that of autosomal chromosomes. In the euchromatic and transcriptionally active domain, autosomal chromosomes pair, synapse and undergo the homologous recombination that ensures their accurate segregation in the meiotic divisions. However, the non-homologous X and Y chromosomes are largely unpaired and form a unique heterochromatic and transcriptionally inactive nuclear territory, known as the XY body, which is the focus of this proposal. Mutations causing failure in modification of XY chromatin render males sterile; therefore, appropriate XY chromatin dynamics are essential for successful spermatogenesis. The underlying hypothesis guiding the proposed experiments is that unpaired chromosomes nucleate a unique array of proteins and post-translational protein modifications that together remodel chromatin. Two (2) critical components of this hypothesis will be tested: whether heterochromatization is a property of any unpaired DNA and the nature and role in the XY body of specific proteins and their modifications. First, it is proposed, like the X and Y chromosomes, any unpaired chromosome will be epigenetically modified and transcriptionally silenced by a general meiotic mechanism known as """"""""meiotic silencing by unpaired DNA"""""""" (MSUD). This will be tested in Aim 1 by determining if an unpaired trisomic autosomal chromosome is modified and silenced. Results from this aim will also yield insight into function of the modified chromatin in repair of induced genomic damage, a process that is absolutely essential for producing gametes with intact chromosomes. Second, it is proposed that recognition of unpaired XY chromatin leads to heterochromatization through recruitment of unique proteins and post-translational protein modifications. This hypothesis will be tested in Aim 2 by focusing on modification of XY body proteins by SUMO (small ubiquitin-related modifier). Identification of the substrate proteins will be followed by gene disruption to provide a genetic test of their function in maintenance of the XY body. Results from these aims will advance our knowledge about the meiotic chromatin-based mechanisms that determine nuclear function and ensure genetic fidelity of spermatogenesis.
| Fritsche, Miriam; Reinholdt, Laura G; Lessard, Mark et al. (2012) The impact of entropy on the spatial organization of synaptonemal complexes within the cell nucleus. PLoS One 7:e36282 |
| Reinholdt, Laura G; Czechanski, Anne; Kamdar, Sonya et al. (2009) Meiotic behavior of aneuploid chromatin in mouse models of Down syndrome. Chromosoma 118:723-36 |
| La Salle, Sophie; Sun, Fengyun; Handel, Mary Ann (2009) Isolation and short-term culture of mouse spermatocytes for analysis of meiosis. Methods Mol Biol 558:279-97 |
| Good, Jeffrey M; Handel, Mary Ann; Nachman, Michael W (2008) Asymmetry and polymorphism of hybrid male sterility during the early stages of speciation in house mice. Evolution 62:50-65 |
| La Salle, Sophie; Sun, Fengyun; Zhang, Xiang-Dong et al. (2008) Developmental control of sumoylation pathway proteins in mouse male germ cells. Dev Biol 321:227-37 |
