Error-Prone Chromosome-Mediated Spindle Assembly Favors Chromosome Segregation Defects in Human Oocytes

摘要

Chromosome segregation errors occurring during the meiotic divisions of a human oocyte are the leading cause of pregnancy loss and several genetic disorders. When chromosomes fail to split into perfect halves during meiosis, the embryo cannot survive or will have a genetic defect, such as Down syndrome. Despite the importance of meiosis in human eggs for fertility and human development, the basis for error-prone chromosome segregation is not known. The authors developed an experimental system for ex vivo high-resolution fluorescence microscopy that allowed them to examine human oocytes freshly harvested from women undergoing gonadotropin-stimulated, in vitro fertilization cycles. Through examination of meiosis in more than 100 live human oocytes, an error-prone, chromosome-mediated, spindle assembly mechanism was identified as a major contributor to chromosome segregation defects. Human oocyte spindle assembly was mediated primarily by chromosomes and the small guanosine triphosphatase Ran independent of centrosomes or other microtubule organizing centers in a process requiring about 16 hours. This unusually slow process is in sharp contrast to mitotic spindles and meiotic spindles in mouse oocytes and other species, which rarely become unstable upon establishment of a bipolar spindle, thus rendering meiosis more efficient and less prone to segregation errors. Spindles assembled during meiosis in human oocytes display a high proportion of abnormal kinetochore-microtubule attachments and are intrinsically unstable. Progression into anaphase with abnormal attachments put human oocytes at risk of chromosome segregation errors, providing 1 mechanism for the high rates of aneuploidy.