title: Spindle assembly checkpoint signalling is uncoupled from chromosomal position in mouse oocytes.
abstract: The spindle assembly checkpoint (SAC) averts aneuploidy by coordinating proper bipolar chromosomal attachment with anaphase-promoting complex/cyclosome (APC/C)-mediated securin and cyclin B1 destruction required for anaphase onset. The generation of a Mad2-based signal at kinetochores is central to current models of SAC-based APC/C inhibition. During mitosis, kinetochores of polar-displaced chromosomes, which are at greatest risk of mis-segregating, recruit the highest levels of Mad2, thereby ensuring that SAC activation is proportionate to aneuploidy risk. Paradoxically, although an SAC operates in mammalian oocytes, meiosis I (MI) is notoriously error prone and polar-displaced chromosomes do not prevent anaphase onset. Here we find that Mad2 is not preferentially recruited to the kinetochores of polar chromosomes of wild-type mouse oocytes, in which polar chromosomes are rare, or of oocytes depleted of the kinesin-7 motor CENP-E, in which polar chromosomes are more abundant. Furthermore, in CENP-E-depleted oocytes, although polar chromosomal displacement intensified during MI and the capacity to form stable end-on attachments was severely compromised, all kinetochores nevertheless became devoid of Mad2. Thus, it is possible that the ability of the SAC to robustly discriminate chromosomal position might be compromised by the propensity of oocyte kinetochores to become saturated with unproductive attachments, thereby predisposing to aneuploidy. Our data also reveal novel functions for CENP-E in oocytes: first, CENP-E stabilises BubR1, thereby impacting MI progression; and second, CENP-E mediates bi-orientation by promoting kinetochore reorientation and preventing chromosomal drift towards the poles.
authors.affiliation: Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Liming
authors.initials: L
authors.lastname: Gui
authors.forename: Hayden
authors.initials: H
authors.lastname: Homer
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D020090:Chromosome Segregation / Q000502:physiology*; D056744:Cyclin B1 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D018386:Kinetochores / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D064246:Mad2 Proteins; D051379:Mice; D060172:Morpholinos; D009865:Oocytes / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D064249:Securin; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
chemical_list: C584278:Bub1b protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D056744:Cyclin B1; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D060172:Morpholinos; D064249:Securin; C068688:centromere protein E; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases