APC^FZR1prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing

Abstract

The APC activator FZR1 has a role in controlling the timing of meiosis I spindle assembly. Oocytes lacking FZR1 undergo accelerated meiosis I, associated with earlier spindle assembly checkpoint satisfaction and APCCDC20 activity, resulting in high rates of aneuploidy.

The APC/C in female mammalian meiosis I

“…Recent findings on Fzr1 D/D oocytes provide surprising new insights into how APC/C Cdh1 affects MI progression through acentrosomal spindle assembly (Holt et al 2012). Consistent with APC/C Cdc20 being the target of inhibitory regulation by the SAC (Foley & Kapoor 2013), Cdc20 over-expression can over-ride the SAC in other systems (Hwang et al 1998, Mondal et al 2007).…”

“…Consistent with APC/C Cdc20 being the target of inhibitory regulation by the SAC (Foley & Kapoor 2013), Cdc20 over-expression can over-ride the SAC in other systems (Hwang et al 1998, Mondal et al 2007). Unexpectedly, however, although Cdc20 levels were nearly 25-fold higher in Fzr1 D/D oocytes, Cdc20 stabilisation per se was not the main driver for earlier anaphase I-onset observed in such oocytes (Holt et al 2012). If it were, then one would predict that APC/C Cdc20 would become active even in the face of ongoing SAC signalling.…”

“…Further investigation of Fzr1 D/D oocytes revealed that earlier onset of anaphase I was in fact related to earlier satisfaction of the SAC brought about by a faster rate of spindle assembly that was accompanied by earlier establishment of stable kMt attachments as determined by earlier redistribution of Mad2 from kinetochores to spindle poles. The authors examined the possibility that accelerated Cdk1 activation in Fzr1 D/D oocytes secondary to cyclin B1 stabilisation might account for their findings but observed similarly accelerated spindle assembly with or without the Cdk1-specific inhibitor, flavopiridol (Holt et al 2012).…”

“…Hec1-dependent cyclin B2 stabilisation is important for early-stage spindle assembly after which preliminary evidence suggests that kinetochore re-orientation, in part mediated by Hec1-and CENP-E-dependent kinetochore functions (Gui & Homer 2012, supports late-stage bipolarisation, a model that will require further investigation. It is hypothetically possible that Hec1 stabilisation in Fzr1 D/D oocytes helps to promote the accelerated spindle assembly and in particular, faster kMt attachment formation, that are observed (Holt et al 2012), but this remains to be formally tested. The schematic therefore incorporates APC/C Cdh1 targets that act as 'spindle assembly factors', which may or may not turn out to include Hec1/cyclin B2.…”

Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice

“…22,31 For quantitative analysis of kinetochore Sgo2, Mad2, and pAurora C, oocytes were double stained with ACA, performed on the same day, and z-stacks of 1 μm z-resolution were acquired using identical settings. All images were analyzed using ImageJ (NIH, Bethesda), and fluorescence calculation was performed as previously described with modifications 31,72 (Fig. S1C).…”