Studies of cyclin A1 and the regulation of the male meiotic cell cycle in the mouse

The work described in this thesis investigated the function of cyclin A1 during murine spermatogenesis, furthering the current understanding of molecular regulation of mammalian meiosis in general. The expression of regulators of the mitotic G2/M transition was characterised during murine spermatogenesis. The expression of cyclin A2 is restricted to the mitotic proliferation phase of germ cells, suggesting the function of cyclin A2 in such mitotic cycles is similar to that in somatic cells. However, subtle differences are observed. In germ cells, cyclin A2 persists until anaphase, whereas in cultured somatic cells, it is being degraded at prometaphase. On the other hand, the expression of cyclin A2 in preleptotene cells implicates that it regulates the pre-meiotic DNA replication. During the meiotic cycle, expression of B-type cyclins and Cdc25C precedes that of cyclin A1. Cyclin B1 and Cdc25C are already present in the nucleus before the onset of cyclin A1 expression. These observations suggest that the temporal and spatial expression of B-type cyclins and Cdc25C is unlikely to be regulated by a cyclin A1-associated function. Cyclin A1, in contrast, only becomes detectable at the end of prophase I indicating that it is dispensable for the meiotic recombination. To define possible function of cyclin A1, the precise point of spermatogenic arrest in Ccna1-null mice was determined. Most spermatocytes arrest at diplotene/diakinesis, while a minority progresses to metaphase/anaphase I with nuclear envelope breakdown, the presence of MPM-2 epitopes, and the phosphorylation of histone H3 on condensed chromosomes. The temporal and spatial expression of B-type cyclins and Cdc25C remains unchanged in the absence of cyclin A1. These findings suggest that cyclin A1 does not regulate the prophase to metaphase transition in meiosis I.