Abstract
Accurate chromosome segregation during mitosis and meiosis is facilitated by a regulatory complex known as the Anaphase Promoting Cyclosome (APC), an ubiquitin ligase complex that tags proteins with ubiquitin. Subsequently targeted proteins are recognised by the 26S proteosome and degraded. In mammalian cells, two temporally regulated co-activators are required for the APC to function; fizzy and fzr1. In studies of female oocyte development fzr1 has been demonstrated to play an important role in maintaining G2 arrest during meiosis by controlling spatial levels of the cell cycle protein Cyclin B1 but the role of Fzr1 in spermatogenesis remains unknown. Germ cell specific conditional knockout fzr1mice were generated using the DDX4-Cre and flox/flox fzr1 mouse lines and initial gross morphological analysis indicated that at 7 weeks of age null mice possessed significantly smaller testes (21.81mg ± 0.23mg) when compared to heterozygote (99.86mg ± 1.58mg) and wildtype littermates (93.06mg ± 1.16mg) n = 3 P < 0.0001. Quantitative gene expression analysis confirmed almost complete absence of fzr1 transcript in testes (20-fold decrease) in comparison to wild-type. Immunoblotting and immunohistochemistry revealed no expression of Fzr1 protein in meiotic and post meiotic germ cells when compared to heterozygote and wild type littermates. Histomorphological analysis of testes tissue sections revealed Fzr1 null males exhibited spermatogenic arrest and a complete absence of round spermatids with concomitant apoptosis in the residual spermatocytes. Epididymal examination confirmed a complete lack of mature spermatozoa in the cauda epididymis of null males. In contrast, both wild type and heterozygote mice displayed normal spermatogenesis and epididymal sperm analysis indicated no distinguishable differences in seminal characteristics with normal motility, morphology and sperm-zona binding capacity. Based on these observations we hypothesise that Fzr1 plays a significant role in the establishment and maintenance of meiosis possibly through regulation of key cell cycle proteins.
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