Meiotic Chromsome Pairing in C. elegans

Meiosis is the specialized division required to half and recombine the chromosomal content prior to gamete fusion. One round of replication is succeeded by two divisions. The first is unique in that the parental chromosomes get separated. During the prolonged prophase of meiosis I a physical connection between the parental homologues is established which facilitates their segregation to opposite poles along the meiotic spindle. Failure to establish this connection leads to chromosome mis-segregation and aneuploidy. The focus of this project is directed towards the identification of genes and their encoded proteins that contribute to early meiotic events, namely the recognition and pairing of homologous chromosomes, the prerequisite for crossover recombination of homologues. Recently, a special allele of the nuclear envelope protein mtf-1/sun-1 in C. elegans was isolated by us. Characterization of this allele allowed us to show its involvement in homologue sorting. We also demonstrated that mtf-1/sun-1 acts upstream of, or is even part of a restriction-point that monitors synapsis to take place only between respective homologues. Based on our observations we propose that the nuclear/cytoplasmic link which possibly mediates chromosome movement via the microtubule/dynein cytoskeleton is missing in mtf-1(jf18) bearing the mutated SUN domain. In the present project we would like to extend our studies to elucidate the molecular mechanism underlying the defect of this special allele mutated in the SUN-domain. Furthermore, we would like to identify other components crucial for the regulation of proper homologue sorting using MTF-1/SUN-1 as a starting point.

Meiosis is the specialized cell division that is essential for the generation of haploid germ cells. It not only compensates for the doubling of chromosome number after fertilization but it also generates genetic diversity by reciprocal exchange of paternal and maternal chromosomes. Defects in the meiotic cell divisions lead to deposition of too many or too few chromosomes into germcells and are thus the leading cause of miscarriages and birth defects. Faithful chromosome segregation is supported by a linkage between the parental homologs. Once homologous chromosomes have found each other, a proteinacious structure, the synaptonemal complex, is established between them. At the same time chromosomes are attached to the nuclear envelope via one end and get moved by a movement apparatus outside the nucleus through the connection of the SUN/KASH bridge. We found that disturbing this connection abrogates movement. Interfereing with SUN-dependent movement leads to the establishment of the synaptonemal complex between non-homologous chromosomes, implying that these forces are necessary for parental chromosomes to find each other and repel wrong interactions. Once all chromosomes have found their homologous partner, movement is ceased and genetic exchange can take place. Here we have not only analyzed chromosome movement in vivo, but also studied the properties of the SUN-domain protein Matefin/SUN- 1 which is central to the SUN/KASH bridge during the time-window of chromosome movement. Our results also depict a regulatory mechanism that defines the time window, in which chromosome movement takes place.