Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: The APC/C activator FZR1 coordinates the timing of meiotic resumption during prophase I arrest in mammalian oocytes. Holt JE et al. FZR1, an activator of the anaphase-promoting complex/cyclosome (APC/C), is recognized for its roles in the mitotic cell cycle. To examine its meiotic function in females we generated an oocyte-specific knockout of the Fzr1 gene (Fzr1 null). The total number of fully grown oocytes enclosed in cumulus complexes was 35-40% lower in oocytes from Fzr1 null mice and there was a commensurate rise in denuded, meiotically advanced and/or fragmented oocytes. The ability of Fzr1 null oocytes to remain prophase I/germinal vesicle (GV) arrested in vitro was also compromised, despite the addition of the phosphodiesterase milrinone. Meiotic competency of smaller diameter oocytes was also accelerated by Fzr1 loss. Cyclin B1 levels were elevated ~5-fold in Fzr1 null oocytes, whereas securin and CDC25B, two other APC/C(FZR1) substrates, were unchanged. Cyclin B1 overexpression can mimic the effects of Fzr1 loss on GV arrest and here we show that cyclin B1 knockdown in Fzr1 null oocytes affects the timing of meiotic resumption. Therefore, the effects of Fzr1 loss are mediated, at least in part, by raised cyclin B1. Thus, APC/C(FZR1) activity is required to repress cyclin B1 levels in oocytes during prophase I arrest in the ovary, thereby maintaining meiotic quiescence until hormonal cues trigger resumption.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: APCFZR1 prevents non-disjunction in mouse oocytes by controlling meiotic spindle assembly timing. Holt JE et al. FZR1 is an APC activator best known for its role in the mitotic cell cycle at M-Phase exit, G1, and in maintaining genome integrity. Previous studies have also established that it prevents meiotic resumption, equivalent to the G2/M transition. Here we report that mouse oocytes lacking FZR1 undergo passage through meiosis I that is accelerated by ~1 h, and this is due to an earlier onset of Spindle Assembly Checkpoint (SAC) satisfaction and APC(CDC20) activity. However, loss of FZR1 did not compromise SAC functionality, instead earlier SAC satisfaction was achieved because the bipolar meiotic spindle was assembled more quickly in the absence of FZR1. This novel regulation of FZR1 on spindle assembly led to premature bivalent attachment to microtubules and loss of kinetochore bound MAD2. Bivalents however were observed to congress poorly leading to non-disjunction rates of 25%. We conclude that in mouse oocytes FZR1 controls the timing of assembly of the bipolar spindle and in so doing the timing of SAC satisfaction and APC(CDC20) activity. This study implicates FZR1 as a major regulator of prometaphase whose activity helps prevent chromosome non-disjunction.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: The Anaphase-Promoting Complex activator Fizzy-Related-1 (FZR1) is involved in the establishment of a single mitotic spindle in 1-cell embryos and in the mitotic divisions of early mammalian embryos. Seah MK et al. In early embryos of a number of species the Anaphase-Promoting Complex (APC), an important cell cycle regulator, requires only CDC20 for cell division. In contrast FZR1, a non-essential gene in many cell types, is thought to play a role in APC activation at later cell cycles, and especially in endoreplication. In keeping with this, FZR1 knockout mouse embryos show normal preimplantation development but die due to a lack of endoreplication needed for placentation. However, interpretation of the role of FZR1 during this period is hindered by the presence of maternal stores. Here, therefore, we used an oocyte-specific knockout to examine FZR1 function in early mouse embryo development. Maternal FZR1 was not critical for completion of meiosis, and furthermore viable pups were born to these 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 ?-H2AX foci, consistent with fragmented DNA. A prominent feature of such embryos was a 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 maintainence of genomic integrity during the mitotic divisions of early mammalian embryos.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: The APC/C activator FZR1 is essential for meiotic prophase I in mice. Holt JE 2014 et al. Fizzy-related 1 (FZR1) is an activator of the Anaphase promoting complex/cyclosome (APC/C) and an important regulator of the mitotic cell division cycle. Using a germ-cell-specific conditional knockout model we examined its role in entry into meiosis and early meiotic events in both sexes. Loss of APC/C(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 FZR1? 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. /////////////////////////