How separated sisters get bad connections

Accurate chromosome segregation depends on chromosomes acquiring correctly configured attachments to microtubules of the spindle apparatus via multi-protein super-complexes that assemble on centromeric DNA called kinetochores. 1 in the correct attachment configuration, kinetochore pairs attach exclusively to opposite spindle poles (Fig. 1). Mis-attachments usually lead to imbalanced forces acting on chromosomes that manifest as misalignment on the spindle and, if left uncorrected, as aberrant separation at anaphase. Chromosome segregation during meio-sis i—which involves separating homologous chromosomes—is notoriously error-prone in human oocytes, especially with advancing female age, and accounts for the overwhelming majority of human aneuploidy that underpin adverse events such as miscarriage and birth defects. During meiosis i, sister kineto-chores of each homolog should function as a coherent unit and not as independent entities as in mitosis or meiosis ii (Fig. 1). The fraction of the molecular glue known as cohesin that is located in the centromere region constrains sister kinetochores to act as a functional unit during meiosis i and is therefore important for enabling each homo-log to become attached to only one spindle pole (monopolar attachment). 2 Cohesin has become a hotbed of interest, since cohesin levels were found to decay in oocytes with aging and to be associated with resolution of meiosis i sister kinetochores into distinct units. 3 The expectation was that relaxation of constraints would lead to uncoupled sister kinetochore behavior and to chaotic attachments to opposite spindle poles (see Fig. 1), thereby markedly increasing the risk for aberrant chromosome segregation and accounting for female age-related increases in aneuploidy. This has not been an easy problem to tackle, because visualizing kinetochore–microtubule (kMt) attachments at the resolution required for meaningful analysis is an extremely challenging prospect in oocytes due to their large volumes and high spindle microtubule density. shomper et al. have taken on this challenge and meticulously compared kMt attachments in oocytes from younger female mice (6 wk) with those in aged oocytes from females 15–17-mo-old, when sister kineto-chore separation had become a prominent feature indicative of substantial deterioration of centromeric cohesion. 4 They found that aged oocytes had increased chromosomal misalignment defects. Also more pronounced in aged oocytes were mis-attachment con-figurations—lateral attachments and attachments of sister kinetochores to both spindle poles (which the authors termed meiotic-merotelic)—with concomitant reductions in correct monopolar attachment. interestingly, although separated sisters formed meiotic-merotelic attachments (see Fig. 1) more often than unified sisters, their overall involvement in such mis-attachments was …