Reproduction Abstracts

Fizzy-related 1 (FZR1) is one of two known activators of the anaphase promoting complex (APC) and a well-established important regulator of the mitotic cell cycle. In a germ-cell-specific (DDX4-cre) conditional knockout model we examined the role of FZR1 in germ cell development with particular emphasis on the entry into meiosis and early meiotic events. Loss of APC FZR1 activity in the male germline led to both a mitotic and a meiotic cell defect resulting in sterility through the complete absence of mature spermatozoa. Spermatogonia in the prepubertal testes displayed abnormal proliferation and delayed entry into meiosis. Although early meiotic recombination events were initiated, male germ cells failed to progress beyond zygotene stage of meiosis and underwent apoptosis. APC FZR1 loss was also associated with elevated cyclin B1 levels in spermatogonia and spermatocytes, indicating that CDK1 may trigger apoptosis. In contrast, the FZR1 null female mice were subfertile, with premature ovarian failure by 20 weeks of age. Initially a large loss of oocytes occurred embryonically, around the time of the zygotene-pachytene transition, similar to that observed in males. In addition, in post natal folliculogenesis the transition of primordial follicles into the growing follicle pool was abnormal and resulted in premature depletion of the primordial follicle pool. We have established that APC FZR1 is an essential regulator of spermatogonial proliferation and in early meiotic prophase I in both the male and female germline, and in post natal follicular development, and conclude that FZR1 is important in establishing and maintaining the reproductive health of adult male and female mammals.