Mechanism of spindle pole organization and instability in human oocytes

• Published in: Science (American Association for the Advancement of Science) Vol. 375; no. 6581; p. eabj3944
• Main Authors: So, Chun, Menelaou, Katerina, Uraji, Julia, Harasimov, Katarina, Steyer, Anna M., Seres, K. Bianka, Bucevičius, Jonas, Lukinavičius, Gražvydas, Möbius, Wiebke, Sibold, Claus, Tandler-Schneider, Andreas, Eckel, Heike, Moltrecht, Rüdiger, Blayney, Martyn, Elder, Kay, Schuh, Melina
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 11.02.2022
• Subjects: 1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism; Accuracy; Aneuploidy; Animals; Assembly; Cancer; Cattle; Cell Cycle Proteins - metabolism; Centrosomes; Chemical composition; Chromosomes; Comparative analysis; Crosslinking; Depletion; Down Syndrome; Down's syndrome; Dynactin Complex - metabolism; Dynein; Dyneins - metabolism; Eggs; Embryogenesis; Embryonic growth stage; Errors; Female; Fidelity; Gametocytes; Genetic disorders; Human performance; Humans; Imaging; Infertility; Kinesin; Kinesins - deficiency; Kinesins - genetics; Kinesins - metabolism; Localization; Macromolecules; Mammals; Maturation; Meiosis; Mice; Microtubule-Associated Proteins - metabolism; Microtubule-Organizing Center - physiology; Microtubule-Organizing Center - ultrastructure; Microtubules; Microtubules - metabolism; Molecular motors; Motor activity; Oocytes; Oocytes - physiology; Oocytes - ultrastructure; Poles; Pregnancy; Proteins; Recombinant Proteins - metabolism; Reproductive technologies; RNA-mediated interference; Somatic cells; Spindle Apparatus - physiology; Spindle Apparatus - ultrastructure; Spindle Poles - physiology; Spindle Poles - ultrastructure; Spindles; Stability; Swine
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abj3944

Human oocytes are prone to assembling meiotic spindles with unstable poles, which can favor aneuploidy in human eggs. The underlying causes of spindle instability are unknown. We found that NUMA (nuclear mitotic apparatus protein)–mediated clustering of microtubule minus ends focused the spindle poles in human, bovine, and porcine oocytes and in mouse oocytes depleted of acentriolar microtubule-organizing centers (aMTOCs). However, unlike human oocytes, bovine, porcine, and aMTOC-free mouse oocytes have stable spindles. We identified the molecular motor KIFC1 (kinesin superfamily protein C1) as a spindle-stabilizing protein that is deficient in human oocytes. Depletion of KIFC1 recapitulated spindle instability in bovine and aMTOC-free mouse oocytes, and the introduction of exogenous KIFC1 rescued spindle instability in human oocytes. Thus, the deficiency of KIFC1 contributes to spindle instability in human oocytes. Chromosomal errors in human eggs are a leading cause of miscarriages and infertility. These errors result from chromosome missegregations during the maturation of oocytes into eggs. Chromosome segregation is driven by the spindle, a macromolecular machinery that pulls chromosomes apart. However, human oocytes often assemble unstable spindles, favoring chromosome missegregations. So et al . discovered that human oocyte spindles are unstable because they are deficient in the molecular motor KIFC1. KIFC1 stabilizes spindles in other mammalian oocytes and in cancer cells. By introducing exogenous KIFC1, the authors were able to increase the fidelity of spindle assembly and chromosome segregation in human oocytes. —SMH Human oocytes have unstable meiotic spindles compared with oocytes from other mammals because of the lack of the molecular motor KIFC1.