The role of HIM-19 in C. elegans meiosis

Successful homologous chromosome recognition is a precondition for subsequent synapsis and crossover recombination in meiosis. The mechanisms how homologous chromosomes recognize and find each other are still poorly understood. The model system of Caenorhabditis elegans offers the advantage that chromosome pairing and recombination are largely independent processes and can therefore be well studied. From a previous genetic screen we have isolated a candidate mutant, him-19, impaired in homolog recognition. Female meiosis is more affected by this mutation than male meiosis and the mutant phenotype is more severe in older worms. Current analysis of the him-19 gene has focused on phenotypic and genetic interaction analysis that allowed us to assign a role in the homolog pairing process to him-19. With this project we aim to reach further in placing him-19 in an exact step in a given genetic pathway. Specifically, we attempt to understand the protein interaction network of factors that cooperate with HIM-19 during meiotic prophase I.

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. Increasing maternal age has been attributed to a striking increase of chromosome mis-segregation. Therefore it is of great interest to study meiotic processes that are subjected to age dependent deterioration. From a screen for meiotic Caenorhabditis elegans chromosome mis-segregation mutants we identified a novel gene, him-19, with multiple functions in prophase of meiosis I which we studied during the course of this project. Mutant him-19 animals show a reduction in pairing of homologous chromosomes and subsequent bivalent formation. They are defective in chromosome end mobilization, DNA double strand break formation, and synaptonemal complex formation. Ultimately, mutation of him-19 leads to chromosome mis-segregation and reduced offspring viability. The observed defects suggest that HIM-19 seems to be engaged in an early meiotic event, resembling in this respect the regulator kinase CHK-2. Remarkably, him and other phenotypes in this mutant aggravate with increasing maternal age. It is conceivable that the him-19 mutation accelerates the normal ageing effects on meiosis, causing increased chromosomal nondisjunction in aged C. elegans. Further characterization of him-19 could contribute to our understanding of age-dependent meiotic defects in humans.