title: Human oocytes. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes.
abstract: Aneuploidy in human eggs is the leading cause of pregnancy loss and several genetic disorders such as Down syndrome. Most aneuploidy results from chromosome segregation errors during the meiotic divisions of an oocyte, the egg's progenitor cell. The basis for particularly error-prone chromosome segregation in human oocytes is not known. We analyzed meiosis in more than 100 live human oocytes and identified an error-prone chromosome-mediated spindle assembly mechanism as a major contributor to chromosome segregation defects. Human oocytes assembled a meiotic spindle independently of either centrosomes or other microtubule organizing centers. Instead, spindle assembly was mediated by chromosomes and the small guanosine triphosphatase Ran in a process requiring ~16 hours. This unusually long spindle assembly period was marked by intrinsic spindle instability and abnormal kinetochore-microtubule attachments, which favor chromosome segregation errors and provide a possible explanation for high rates of aneuploidy in human eggs.
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Holubcová
authors.affiliation: Bourn Hall Clinic, Bourn, Cambridge CB23 2TN, UK.
authors.forename: Martyn
authors.initials: M
authors.lastname: Blayney
authors.affiliation: Bourn Hall Clinic, Bourn, Cambridge CB23 2TN, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Elder
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. mschuh@mrc-lmb.cam.ac.uk.
authors.forename: Melina
authors.initials: M
authors.lastname: Schuh
mesh_terms: D000705:Anaphase; D000782:Aneuploidy; D000818:Animals; D002478:Cells, Cultured; D020090:Chromosome Segregation; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D008540:Meiosis; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D022101:Microtubule-Organizing Center / Q000378:metabolism; D009865:Oocytes / Q000473:pathology*; D008941:Spindle Apparatus / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; C120587:RAN protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020931:ran GTP-Binding Protein