Nabeshima Group

Our primary research interest is the chromosome dynamics during gametes (sperms and eggs) production. Gametes are the only cells that are passed to the next generation, and their successful development from germline stem cells is of paramount importance in sexual reproduction. During gametogenesis, chromosomes behave in a unique way reducing ploidy by half from diploid to haploid. This process is called meiosis. After the fertilization where a sperm and an egg unite, a diploid genome is restored, and the individuals of the next generation inherit exact two sets of chromosomes. If the gametes fail to carry a correct haploid genome, anauploid pregnancy occurs, which causes birth defects or miscarriages, and mental retardation in humans. Therefore, the mechanism that supports accurate chromosome dynamics during meiosis is critical for successful sexual reproduction. However, how this highly accurate process is achieved has just started emerging. We are focusing on this fundamental question by using a modern model organism, C. elegans, with many both classical and modern techniques such as genetics, biochemistry, cytology, functional genomics, and high resolution 3D microscopy.

In order to accurately reduce ploidy, germ cells first correctly make a pair of homologous chromosomes for all chromosomes (homologous pairing). Two sets of homologous chromosomes are very similar to each other but not exactly the same: one set is from the father, the other from the mother. In this process, chromosomes recognize and associate with each other along their entire length (homologous alignment). This association is followed by stabilization by synaptonemal complex (SC), which is proteineceous structure that stabilize the association between two chromosomes. Then homologous chromosomes are physically linked by reciprocal homologous recombination (crossing over). Finally, cells undergo reductional division to halve the chromosome number. Among these processes, initial association and recognition of homologous chromosomes are the least well understood. How do chromosomes recognize their homology? How do chromosomes stabilize their association? Although the first cytological report on homologous paring was made more than a century ago and since then many researchers have tried to reveal the mechanism of this process, it remains as a major unsolved problem in biology. We are tackling this long-standing enigma with a modern biological approach.

We recently published a paper that describes a role of the chromodomain protein MRG-1 in presynaptic alignment in C. elegans. Since MRG-1 is a potential histone modifier and our data strongly support its direct role in homologous pairing, we are now investigating the mechanistic relationship between histone modification and the homologous pairing process. Since our data also support the exciting possibility that MRG-1 specifically contributes to homology recognition between chromosomes, we are using the mrg-1 mutant as a model to investigate cellular processes that enables accurate homology recognition. Our unique approach to these problems includes methods for high-resolution three-dimensional microscopy. We visualize individual chromosomes by chromosome paint in order to precisely determine their identity and analyze a homology recognition process. This chromosome paint is further combined with immunofluorescent staining to investigate the state of chromosome pairing and formation of protein complexes on the chromosome. These newly-developed methods now allow us to observe unprecedented detail of the chromosomal architecture and organization with the unambiguous identify of the chromosomes. We are also applying these methods to investigate other factors that we have newly identified in our screen to be required for homologous pairing. Another current focus of our lab is to understand the checkpoint mechanism that ensures the production of high quality gametes, particularly in relation to the proper chromosome interaction. We have found that a possible meiotic quality control mechanism compensates for failure in accurate homology recognition process. Understanding of such a mechanism likely contributes to improving reproductive health in humans.