https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21729 Fzr1 knockout mouse embryos show normal preimplantation development but die due to a lack of endoreduplication needed for placentation. However, interpretation of the role of FZR1 during this period is hindered by the presence of maternal stores. In this study, therefore, we used an oocyte-specific knockout to examine FZR1 function in early mouse embryo development. Maternal FZR1 was not crucial for completion of meiosis, and furthermore viable pups were born to Fzr1 knockout females mated with normal males. However, in early embryos the absence of both maternal and paternal FZR1 led to a dramatic loss in genome integrity, such that the majority of embryos arrested having undergone only a single mitotic division and contained many γ-H2AX foci, consistent with fragmented DNA. A prominent feature of such embryos was the establishment of two independent spindles following pronuclear fusion and thus a failure of the chromosomes to mix (syngamy). These generated binucleate 2-cell embryos. In the 10% of embryos that progressed to the 4-cell stage, division was so slow that compaction occurred prematurely. No embryo development to the blastocyst stage was ever observed. We conclude that Fzr1 is a surprisingly essential gene involved in the establishment of a single spindle from the two pronuclei in 1-cell embryos as well as being involved in the maintenance of genomic integrity during the mitotic divisions of early mammalian embryos.]]> Wed 11 Apr 2018 11:35:19 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21158 FZR1 activity in the male germline led to both a mitotic and a meiotic testicular defect resulting in infertility due to the absence of mature spermatozoa. Spermatogonia in the prepubertal testes of such mice had abnormal proliferation and delayed entry into meiosis. Although early recombination events were initiated, male germ cells failed to progress beyond zygotene and underwent apoptosis. Loss of APC/C^FZR1 activity was associated with raised cyclin B1 levels, suggesting that CDK1 may trigger apoptosis. By contrast, female FZR1Δ mice were subfertile, with premature onset of ovarian failure by 5 months of age. Germ cell loss occurred embryonically in the ovary, around the time of the zygotene-pachytene transition, similar to that observed in males. In addition, the transition of primordial follicles into the growing follicle pool in the neonatal ovary was abnormal, such that the primordial follicles were prematurely depleted. We conclude that APC/C^FZR1 is an essential regulator of spermatogonial proliferation and early meiotic prophase I in both male and female germ cells and is therefore important in establishing the reproductive health of adult male and female mammals.]]> Sat 24 Mar 2018 08:00:18 AEDT ]]>