Oocyte-Specific Differences in Cell-Cycle Control Create an Innate Susceptibility to Meiotic Errors

Abstract

Summary Segregation of homologous chromosomes at the first meiotic division (MI) is facilitated by crossovers and by a physical constraint imposed on sister kinetochores that allows them to make a monopolar attachment to the MI spindle. Recombination failure or premature separation of homologs results in univalent chromosomes at MI, and univalents constrained to form monopolar attachments should be inherently unstable and trigger the spindle assembly checkpoint (SAC) [1]. Although this appears to be the case in the male [2–5], the presence of one or several univalents does not cause cell cycle delay or arrest in the mammalian oocyte [6, 7]. The spindle assembly portion of the SAC appears to function normally in the oocyte [8–10], but two hypotheses have been proposed to explain the surprising lack of response to univalent chromosomes: 1) reduced stringency of the oocyte SAC to aberrant chromosome behavior [7], and 2) the ability of univalents to form bipolar attachments that satisfy SAC requirements [6]. Results of the present study of Mlh1 mutant mice demonstrate that metaphase alignment is not a prerequisite for anaphase onset and provide strong evidence that MI spindle stabilization and anaphase onset requires stable bipolar attachment of a critical mass - but, importantly, not all - chromosomes. We postulate that subtle differences in SAC-mediated control make the human oocyte inherently error-prone and provide a biological explanation for the high rate of aneuploidy in humans.

Error-prone mammalian female meiosis from silencing the spindle assembly checkpoint without normal interkinetochore tension

“…This outcome is strikingly different from the chronic delay seen in mouse oocytes with defective spindle architecture (4,6,12) and in insect spermatocytes (13,23,24). Indeed, efforts using micromanipulation of chromosomes in centriolar male meiosis in insects had initially concluded that tension generated by spindle forces between kinetochores of bivalents was required to silence SAC signaling by those kinetochores, thereby permitting advance to anaphase (12,23).…”

“…Evidence of missegregation in mouse MI of univalent, achiasmatic chromosomes after blocking almost all homologous recombination (by deletion of Mlh1) led Hunt and colleagues (12) to postulate that the oocyte SAC was unable to ensure stable bipolar attachment of bivalents before anaphase onset. Our evidence now demonstrates that the presence in mouse oocytes of poorly aligned chromosomes with sharply reduced interkinetochore tension does not delay, much less prevent, onset of meiotic anaphase I.…”

“…Studies using oocytes from females lacking a key synaptonemal complex gene (Scp3) have shown that passage through MI can occur in the presence of a few univalent chromosomes (10). Suppressing meiotic recombination in mouse oocytes lacking Mhl1, a protein essential for meiotic recombination, leads to premature separation of most homologs and major abnormalities in meiotic spindle assembly accompanied by chronic SAC-dependent meiotic arrest (11) or delay (12), depending on the genetic background. Efforts in male meiosis in insects have established that despite attachment to spindle microtubules, a single unpaired homolog provokes chronic SACdependent meiotic arrest (13) that is overcome by application of mechanical tension to the kinetochore of the unpaired homolog.…”

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

“…25 We did not detect a specific localization of Chk1 to the kinetochores, which may be another explanation for the different result. A recent study showed that metaphase alignment is not a requirement for anaphase onset, 39 and we propose these subtle differences in SAC regulation between meiosis in oocytes and mitosis in somatic cells may also contribute to (Abcam; 1:500) or mouse monoclonal anti-β-actin (Zhong Shan Jin Qiao; 1:1,000) antibodies at 4°C overnight. After washing three times in TBST, the membranes were incubated with appropriate IRDye 680RD or IRDye 800CW conjugated secondary antibodies (LI-COR Biotechnology) at room temperature for 1 h. Following three more washes in TBST, the membranes were examined by Odyssey infrared imaging system (LI-COR Biotechnology).…”

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

“…Robust checkpoints operate during mammalian spermatogenesis to eliminate most chromosomally imbalanced sperm [16]. Surprisingly, human oocytes and embryos, especially those derived from older individuals, fail to implement discriminating cell cycle checkpoints [18] and as a result allow for the propagation of aneuploid cells with both potential beneficial and deleterious effects to the somatic organism [19].…”