APC(FZR1) prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing.
FZR1 is an anaphase-promoting complex (APC) activator best known for its role in the mitotic cell cycle at M-phase exit, in G1, and in maintaining genome integrity. Previous studies 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 spindle assembly by FZR1 led to premature bivalent attachment to microtubules and loss of kinetochore-bound MAD2. Bivalents, however, were observed to congress poorly, leading to nondisjunction 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 to prevent chromosome nondisjunction.
School of Biomedical Sciences, University of Newcastle, Callaghan, NSW 2308, Australia. Janet.holt@newcastle.edu.au
Janet E
JE
Holt
Simon I R
SI
Lane
Phoebe
P
Jennings
Irene
I
García-Higuera
Sergio
S
Moreno
Keith T
KT
Jones
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D064199:Cdc20 Proteins; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism; D064246:Mad2 Proteins; D008540:Meiosis / Q000187:drug effects; D008677:Metaphase / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D009630:Nondisjunction, Genetic / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D009865:Oocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D008941:Spindle Apparatus / Q000378:metabolism*; D013997:Time Factors
D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D056744:Cyclin B1; C577585:Fzr1 protein, mouse; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C572046:TPX2 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C521052:Kif11 protein, mouse; D016547:Kinesins; D015739:Nocodazole