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Summary Background The growing trend for women to postpone childbearing has resulted in a dramatic increase in the incidence of trisomic pregnancies. Maternal age-related miscarriage and birth defects are predominantly a consequence of chromosome segregation errors during the first meiotic division (MI), which involves the segregation of replicated recombined homologous chromosomes. Despite the importance to human reproductive health, the events precipitating female age-related meiotic errors are poorly understood. Results Here we use a long-lived wild-type mouse strain to show that the ability to segregate chromosomes synchronously during anaphase of MI declines dramatically during female aging. This is preceded by depletion of chromosome-associated cohesin in association with destabilization of chiasmata, the physical linkages between homologous chromosomes, and loss of the tight association between sister centromeres. Loss of cohesin is not due to an age-related decline in the ability of the spindle checkpoint to delay separase-mediated cleavage of cohesin until entry into anaphase I. However, we find that reduced cohesin is accompanied by depletion of Sgo2, which protects centromeric cohesin during MI. Conclusions The data indicate that cohesin declines gradually during the long prophase arrest that precedes MI in female mammals. In aged oocytes, cohesin levels fall below the level required to stabilize chiasmata and to hold sister centromeres tightly together, leading to chromosome missegregation during MI. Cohesin loss may be amplified by a concomitant decline in the levels of the centromeric cohesin protector Sgo2. These findings indicate that cohesin is a key molecular link between female aging and chromosome missegregation during MI.

Summary To ensure correct meiotic chromosome segregation, sister chromatid cohesion (SCC) needs to be maintained from its establishment in prophase I oocytes before birth until continuation of meiosis into metaphase II upon oocyte maturation in the adult. Aging human oocytes suffer a steep increase in chromosome missegregation and aneuploidy, which may be caused by loss of SCC through slow deterioration of cohesin [1–3]. This hypothesis assumes that cohesin expression in embryonic oocytes is sufficient to provide adequate long-term SCC. With increasing age, mouse oocytes deficient in the meiosis-specific cohesin SMC1β massively lose SCC and chiasmata [3, 4]. To test the deterioration hypothesis, we specifically and highly efficiently inactivated the mouse Smc1 β gene at the primordial follicle stage shortly after birth, when oocytes had just entered meiosis I dictyate arrest. In the adult, however, irrespective of oocyte age, chiasma positions and SCC are normal. Frequency and size of litters prove full fertility even in aged females. Thus, SMC1β cohesin needs only be expressed during prophase I prior to the primordial follicle stage to ensure SCC up to advanced age of mice.

Summary Background Chromatoid bodies (CBs) are characteristic spermatid organelles, which were suggested to function in RNA storage and small RNA processing but whose functions remain largely unknown. CB components include Mili, Miwi, and Tudor domain proteins such as Tdrd6, whose contribution to CB structure and function is elusive. Results We determined gametogenesis stage- and male-specific expression and localization of Tdrd6, identified a C-terminally truncated form as predominant after meiosis I, and demonstrated direct physical interaction of Tdrd6 with the CB components Mili and Miwi. Development from round into elongated spermatids is abrogated in Tdrd6 −/− mice. Their round spermatids bear "ghost" CBs, whose architecture is greatly disrupted. Mael, Miwi, and Mvh do not localize to the Tdrd6-deficient CBs, but retrotransposons are not significantly activated. However, more than 50 miRNAs are more abundant in Tdrd6 −/− testes, as are exemplary pre- and pri-miRNAs. Conclusion We conclude that Tdrd6 is essential for spermiogenesis, for CB structure, and for proper mature and precursor miRNA expression.

Summary The cohesin complex is built upon the SMC1/SMC3 heterodimer, and mammalian meiocytes feature two variants of SMC1 named SMC1α and SMC1β. It is unclear why these two SMC1 variants have evolved. To determine unique versus redundant functions of SMC1β, we asked which of the known functions of SMC1β can be fulfilled by SMC1α. Smc1α was expressed under control of the Smc1β promoter in either wild-type or SMC1β-deficient mice. No effect was seen in the former. However, several major phenotypes of SMC1β-deficient spermatocytes were rescued by SMC1α. We observed extended development before apoptosis and restoration of axial element and synaptonemal complex lengths, chromosome synapsis, sex body formation, processing of DNA double-strand breaks, and formation of MLH1 recombination foci. This supports the concept that the quantity rather than the specific quality of cohesin complexes is decisive for meiotic chromosome architecture. It also suggests plasticity in complex composition, because to replace SMC1β in many functions, SMC1α has to more extensively associate with other cohesins. The cells did not complete meiosis but died to the latest at the pachytene-to-diplotene transition. Telomere aberrations known from Smc1β−/− mice persisted, and DNA damage response and repair proteins accumulated there regardless of expression of SMC1α. Thus, whereas SMC1α can substitute for SMC1β in many functions, the protection of telomere integrity requires SMC1β., Highlights • SMC1α can substitute for SMC1β in many meiotic functions • Key for many meiotic functions is the quantity of cohesin, not the specific type • Telomere integrity can be preserved only by SMC1β • In the absence of SMC1β, a DNA damage response is triggered at telomeres, Why are there two SMC1 variants in meiocytes? Biswas et al. asked which of the functions of SMC1β can be fulfilled by SMC1α. Several major phenotypes of SMC1β-deficient spermatocytes were rescued by SMC1α, but telomere deficiencies were not. Thus, whereas SMC1α can substitute for SMC1β in many functions, telomere integrity requires SMC1β.